Benzoic Acid, Benzoic Acid Derivatives and Heteroaryl Carboxylic Acid Conjugates of Hydrocodone, Prodrugs, Methods of Making and Uses Thereof

ABSTRACT

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/076,586, filed Mar. 21, 2016 which is a continuation-in-part of U.S.application Ser. No. 14/817,581, filed Aug. 4, 2015, now U.S. Pat. No.9,549,923, which is a continuation of U.S. application Ser. No.14/534,852, filed Nov. 6, 2014, which is a continuation-in-part of U.S.application Ser. No. 13/888,587, filed May 7, 2013, now U.S. Pat. No.8,927,716, which is a continuation of U.S. application Ser. No.12/828,381, filed Jul. 1, 2010, now U.S. Pat. No. 8,461,137, whichclaims priority to and benefit of U.S. provisional patent applicationSer. No. 61/222,718, filed Jul. 2, 2009, both of which are hereinincorporated by reference in their entireties.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribedfor the treatment of acute and chronic pain. For example, they are alsocommonly used as antitussives. Opioids, however, also produce euphoriaand are highly addictive. As a result, they are often abused withpotentially far reaching social and health related consequences.

Because of the inherent potential for abuse, it is desirable that anypharmaceutical composition containing an opioid agonist be made asabuse-resistant or abuse-deterrent as practical. Illicit users oftenwill attempt to circumvent the extended release properties of opioids byinjecting or otherwise misusing the pharmaceutical composition in orderto achieve an immediate release of the opioid agonist.

Despite their addictive properties and the potential for abuse,morphine-like drugs, particularly, codeine and hydrocodone have beenroutinely prescribed as treatment for severe acute and chronic pain inrecent decades. This is, in part, because there are no alternatives torelieve severe pain (that is resistant to other less potent analgesicssuch as non-steroidal anti-inflammatory drugs (NSAIDS)). In this regard,there is a need to decrease the abuse potential while still achievingpain relief. Thus far, conventional approaches taken, unfortunately,have not provided a solution.

Hydrocodone is an opioid analgesic and antitussive and occurs as fine,white crystals or as crystalline powder. Hydrocodone is a semisyntheticnarcotic analgesic prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is mainly used for reliefof moderate to moderately severe pain. Additionally, it is used as anantitussive in cough syrups and tablets in sub-analgesic doses (e.g.,2.5-5 mg).

Patients taking opioid analgesics such as hydrocodone for pain reliefcan become unintentionally addicted. As tolerance to the opioidsdevelops, more drug is needed to alleviate the pain and generate thesense of well-being initially achieved with the originally prescribeddose. This leads to dose escalation, which if left unchecked can rapidlylead addiction. In some cases patients have become very addicted in aslittle as thirty days.

BRIEF SUMMARY OF THE INVENTION

The present technology utilizes covalent conjugation of the opioidhydrocodone with certain aryl carboxylic acids to decrease its potentialfor causing overdose or abuse by requiring the active hydrocodone to bereleased through enzymatic or metabolic breakdown of the conjugate invivo. The present technology also provides methods of deliveringhydrocodone as conjugates that release the hydrocodone following oraladministration while being resistant to abuse by circuitous routes suchas intravenous (“shooting”) injection and intranasal administration(“snorting”).

The presently described technology in at least one aspect provides aslow/sustained/controlled/extended release composition of conjugatedhydrocodone that allows slow/sustained/controlled/extended delivery ofthe hydrocodone and/or its active metabolite, hydromorphone, into theblood system of a human or animal within a therapeutic window upon, forexample, oral administration. At least some compositions/formulations ofthe current technology can lessen addiction/abuse potential and/or othercommon side effects associated with hydrocodone and similar opioidcompounds, among others.

In one aspect, the present technology provides a composition comprisingat least one conjugate of hydrocodone and at least one benzoic acid, aderivative thereof, or a combination thereof.

In another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least one ligandwherein the ligand is a benzoic acid or derivative thereof, a saltthereof, or a combination thereof, the benzoic acid or derivativethereof having the following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10, such as 1,2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of this aspect, thebenzoic acid or derivative thereof is an aminobenzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In yet another aspect, the present technology provides one or morecompositions or conjugates of hydrocodone for use to treat pain,preferably moderate to severe pain, or for use to reduce or preventoral, intranasal or intravenous drug abuse. In some aspects, theconjugates provide oral, intranasal or parenteral drug abuse resistance.

In a still further aspect, the present technology provides at least oneconjugate or composition of hydrocodone that exhibits a slower rate ofrelease over time and a greater or equal AUC when compared to anequivalent molar amount of unconjugated hydrocodone over the same timeperiod. In other aspects, the conjugate or composition of hydrocodoneexhibits less variability in an oral PK profile when compared tounconjugated hydrocodone. In yet another aspect, at least one conjugateor composition of this aspect of the present technology can exhibitreduced side effects when compared with unconjugated hydrocodone orprevents drug tampering by either physical (e.g., crushing) or chemical(e.g., extraction) manipulation.

In an additional aspect, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC when comparedto an equivalent molar amount of unconjugated hydrocodone. In furtheraspects, at least one conjugate is provided in an amount sufficient toprovide a therapeutically bioequivalent AUC when compared to anequivalent molar amount of unconjugated hydrocodone, but does notprovide a C_(max) spike or has a lower C_(max) than a therapeuticallyequivalent amount of unconjugated hydrocodone. In yet a further aspect,at least one conjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to an equivalent molaramount of unconjugated hydrocodone, but does not provide an equivalentC_(max) spike. In some aspects, at least one conjugate provides anequivalent C_(max) spike when compared to unconjugated hydrocodone.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or conditioninvolving, requiring or mediated by binding of an opioid to one or moreopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or derivative thereof, a saltthereof, or a combination thereof, the benzoic acid or derivativethereof having formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10, such as 1,2, 3, 4, 5, 6, 7, 8, 9, or 10.

In a further aspect, at least one conjugate binds irreversibly to one ormore opioid receptors of the patient.

In an additional aspect, the present technology provides at least onemethod for treating a patient having a disease, disorder or conditioninvolving, requiring or mediated by inhibiting the binding of an opioidto the opioid receptors of the patient, comprising orally administeringto the patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone and at least one benzoic acid or derivativethereof, a salt thereof, or a combination thereof, the benzoic acid orderivative thereof having formula I:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10, such as 1,2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some aspects, the present technology provides at least one conjugatethat reversibly inhibits binding of an opioid to an opioid receptor ofthe patient.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition (such aspain) which can be treated by the binding of an opioid to one or moreopioid receptors of a patient, the method comprising orallyadministering to the patient a pharmaceutically effective amount of atleast one conjugate of hydrocodone and at least one benzoic acid, a saltthereof, a derivative thereof or a combination thereof.

In yet another aspect, the present technology provides at least onemethod for treating a patient having a disease, disorder or condition(such as addiction) which can be treated by inhibiting the binding of anopioid to the opioid receptors of the patient, comprising orallyadministering to the patient a pharmaceutically effective amount of atleast one conjugate of hydrocodone and at least one benzoic acid, a saltthereof, a derivative thereof or a combination thereof.

In yet another aspect, the present technology provides at least onemethod for rehabilitation, such as a step down therapy, of an opioidaddicted patient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.

In a still further aspect, the present technology provides at least onepharmaceutical kit including a specified amount of individual doses in apackage containing a pharmaceutically effective amount of at least oneconjugate of hydrocodone and at least one benzoate, a salt thereof, aderivative thereof or a combination thereof, the benzoate having theformula I:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be independentlyselected from 0 or 1; and x is an integer between 1 and 10, such as 1,2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, the kit furthercomprises instructions for use of the kit in at least one method fortreating or preventing drug withdrawal symptoms or pain in a human oranimal patient.

In another aspect, the present technology provides a pharmaceutical kitincluding a specified amount of individual doses in a package containinga pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof. In some aspects, the kit furtherincludes instructions for use of the kit in at least one method fortreating or preventing drug withdrawal symptoms or pain in a human oranimal patient.

In yet another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof.

In yet another aspect, the present technology provides at least oneconjugate of hydrocodone and at least one heteroaryl carboxylic acid, aderivative thereof, or a combination thereof where at least oneheteroaryl carboxylic acid is selected from formula II, formula III orformula IV,

wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,at least one heteroaryl carboxylic acid is a pyridine derivative.

In some aspects, the present technology provides at least one conjugatethat prevents drug tampering by either physical or chemicalmanipulation.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition requiringor mediated by binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid.

In a further aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition requiringor mediated by binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid, where theheteroaryl carboxylic acid is selected from formula II, formula III orformula IV, wherein formula II, formula III and formula IV are:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10, such as 1, 2, 3,4, 5, 6, 7, 8, 9, or 10.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition requiringor mediated by binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition requiringor mediated by inhibiting binding of an opioid to the opioid receptorsof the patient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid. In someaspects, the heteroaryl carboxylic acid is selected from formula II,formula III or formula IV, wherein formula II, formula III and formulaIV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10, such as 1, 2, 3,4, 5, 6, 7, 8, 9, or 10.

In another aspect, the present technology provides at least one methodfor treating a patient having a disease, disorder or condition requiringor mediated by inhibiting binding of an opioid to the opioid receptorsof the patient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.

In yet another aspect, the present technology provides a pharmaceuticalkit including a specified number of individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof hydrocodone and at least one heteroaryl carboxylic acid, a derivativethereof, or a combination thereof, wherein the heteroaryl carboxylicacid is selected from formula II, formula III or formula IV, whereinformula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,the kit further comprises instructions for use of the kit in at leastone method for treating or preventing drug withdrawal symptoms or painin a human or animal patient.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onebenzoic acid or benzoic acid derivative, a salt thereof, or acombination thereof, the benzoic acid or benzoic acid derivative havingthe following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10, such as 1,2, 3, 4, 5, 6, 7, 8, 9, or 10.

In another aspect, the present technology provides a prodrug comprisingat least one conjugate of hydrocodone and at least one benzoic acid, aderivative thereof, or a combination thereof.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof. In some aspects, the prodrug includes at least one heteroarylcarboxylic acid selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10, such as 1, 2, 3,4, 5, 6, 7, 8, 9, or 10.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onenicotinic acid, a derivative thereof, or a combination thereof.

In some aspects, the prodrug includes an aminobenzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In additional aspects, the current technology is related to acomposition comprising 3.33 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 2.27 mg of hydrocodone.

In additional aspects, the current technology is related to acomposition comprising 4.45 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 3.03 mg of hydrocodone.

In additional aspects, the current technology is related to acomposition comprising 5 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 3.4 mg of hydrocodone.

In other aspects, the current technology is related to a compositioncomprising 6.67 mg of benzoate-hydrocodone hydrochloride (Bz-HC.HCl)which contains a molar equivalent of 4.54 mg of hydrocodone.

In further aspects, the current technology is related to a compositioncomprising 8.9 mg of benzoate-hydrocodone hydrochloride (Bz-HC.HCl)which contains a molar equivalent of 6.06 mg of hydrocodone.

In additional aspects, the current technology is related to acomposition comprising 10 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 6.8 mg of hydrocodone.

In additional aspects, the current technology is related to acomposition comprising 13.34 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 9.08 mg of hydrocodone.

In additional aspects, the current technology is related to acomposition comprising 15 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 10.21 mg ofhydrocodone.

In additional aspects, the current technology is related to acomposition comprising 30 mg of benzoate-hydrocodone hydrochloride(Bz-HC.HCl) which contains a molar equivalent of 20.41 mg ofhydrocodone.

In other aspects, the current technology is related to a compositioncomprising 3.33 mg benzoate-hydrocodone hydrochloride and 162.5 mgacetaminophen (Bz-HC.HCl/APAP, 3.33 mg/162.5 mg) which contains a molarequivalent of 2.27 mg of hydrocodone.

In further aspects, the current technology is related to a compositioncomprising 4.45 mg benzoate-hydrocodone hydrochloride and 216.67 mgacetaminophen (Bz-HC.HCl/APAP, 4.45 mg/216.67 mg) which contains a molarequivalent of 3.03 mg of hydrocodone.

In further aspects, the current technology is related to a compositioncomprising 4.45 mg benzoate-hydrocodone hydrochloride and 325 mgacetaminophen (Bz-HC.HCl/APAP, 4.45 mg/325 mg) which contains a molarequivalent of 3.03 mg of hydrocodone.

In other aspects, the current technology is related to a compositioncomprising 6.67 mg benzoate-hydrocodone hydrochloride and 325 mgacetaminophen (Bz-HC.HCl/APAP, 6.67 mg/325 mg) which contains a molarequivalent of 4.54 mg of hydrocodone.

In further aspects, the current technology is related to a compositioncomprising 8.9 mg benzoate-hydrocodone hydrochloride and 325 mgacetaminophen (Bz-HC.HCl/APAP, 8.9 mg/325 mg) which contains a molarequivalent of 6.06 mg of hydrocodone.

In further aspects, the current technology is related to a compositioncomprising 13.34 mg benzoate-hydrocodone hydrochloride and 650 mgacetaminophen (Bz-HC.HCl/APAP, 13.34 mg/650 mg) which contains a molarequivalent of 9.08 mg of hydrocodone.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1. Chemical structures of hydroxybenzoic acids and benzoic acidderivatives for use in the making of the conjugates of the presenttechnology.

FIG. 2. Chemical structures of aminobenzoic acids for use in the makingof the conjugates of the present technology.

FIG. 3. Chemical structures of aminohydroxybenzoic acids for use in themaking of conjugates of the present technology.

FIG. 4. FIG. 4A is a Table of common hydrocodone products and dosageranges and FIG. 4B is a Table of common hydrocodone products used incough syrups.

FIG. 5. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC (benzoate-hydrocodone), YYFFI-HC(Tyr-Tyr-Phe-Phe-Ile-Hydrocodone) and Diglycolate-HC over time upon oraladministration in rats.

FIG. 6. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, YYFFI-HC, andDiglycolate-HC in rats.

FIG. 7. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and Adipate-HC over time upon intranasaladministration in rats.

FIG. 8. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon intranasal administration of Bz-HC andAdipate-HC in rats.

FIG. 9. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, Nicotinate-HC and Hydrocodone.BT over time uponoral administration in rats.

FIG. 10. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, Nicotinate-HCand Hydrocodone.BT in rats.

FIG. 11. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, 2-ABz-HC and Hydrocodone.BT over time upon oraladministration in rats.

FIG. 12. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, 2-ABz-HC andHydrocodone.BT in rats.

FIG. 13. Synthesis diagrams of conjugates of hydrocodone. FIG. 13Adepicts the synthesis of benzoate hydrocodone. FIG. 13B depicts thesynthesis of nicotinate hydrocodone (nicotinic acid). FIG. 13C depictsthe synthesis of 2-aminobenzoate hydrocodone. FIG. 13D depicts thesynthesis of salicylate hydrocodone.

FIG. 14. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon oral administration in rats.

FIG. 15. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and hydrocodone.BT over time upon oraladministration in dogs.

FIG. 16. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC andhydrocodone.BT in dogs.

FIG. 17. PK profile graph of plasma concentrations of intact Bz-HC andof hydrocodone released from Bz-HC over time upon oral administration indogs.

FIG. 18. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon intravenous administration in rats at 0.30 mg/kg.

FIG. 19. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC over time upon oral administration in rats at sixdifferent dosages.

FIG. 20. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC in rats at sixdifferent dosages.

FIG. 21. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)over time upon single dose, oral administration in fasted humans.

FIG. 22. PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)over time upon single dose, oral administration in fasted humans.

FIG. 23. PK profile graph of plasma concentrations of acetaminophenreleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)over time upon single dose, oral administration in fasted humans.

FIG. 24. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (2×6.67 mg/325 mg) over time upon singledose, oral administration in humans without prior hydrocodone exposure(Day 1) and in humans at steady-state (Day 4).

FIG. 25. PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (2×6.67 mg/325 mg) over time upon singledose, oral administration in humans without prior hydromorphone exposure(Day 1) and in humans at steady-state (Day 4).

FIG. 26. PK profile graph of plasma concentrations of acetaminophenreleased from Bz-HC.HCl/APAP (2×6.67 mg/325 mg) over time upon singledose, oral administration in humans without prior acetaminophen exposure(Day 1) and in humans at steady-state (Day 4).

FIG. 27. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)upon single dose, oral administration in fed and fasted humans.

FIG. 28. PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)upon single dose, oral administration in fed and fasted humans.

FIG. 29. PK profile graph of plasma concentrations of acetaminophenreleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Norco® (7.5 mg/325 mg)upon single dose, oral administration in fed and fasted humans.

FIG. 30. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Vicoprofen® (7.5mg/200 mg) upon single dose, oral administration in fasted humans.

FIG. 31. PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Vicoprofen® (7.5mg/200 mg) upon single dose, oral administration in fasted humans.

FIG. 32. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) upon single dose, oraladministration in fasted humans.

FIG. 33. PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) upon single dose, oraladministration in fasted humans.

FIG. 34. PK profile graph of plasma concentrations of acetaminophenreleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and Ultracet® (37.5 mg/325mg) upon single dose, oral administration in fasted humans.

FIG. 35. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg per tablet) and HB/APAP(7.5 mg/325 mg per tablet) upon single dose, oral administration infasted humans at 4, 8, and 12 tablets, respectively.

FIG. 36 PK profile graph of mean plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (13.34 mg/650 mg) and HB/APAP (15 mg/650mg) upon intranasal administration in fasted humans.

FIG. 37 PK profile graph of mean plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (13.34 mg/650 mg) and HB/APAP (15 mg/650mg) upon oral and intranasal administration in fasted humans.

FIG. 38. PK profile graph of plasma concentrations of hydrocodonereleased from Bz HC.HCl/APAP (6.67 mg/325 mg) upon single dose, oraladministration in fasted humans.

FIG. 39. PK profile graph of plasma concentrations of hydromorphonereleased from Bz HC.HCl/APAP (6.67 mg/325 mg) upon single dose, oraladministration in fasted humans.

FIG. 40. PK profile graph of plasma concentrations of acetaminophenreleased from Bz HC.HCl/APAP (6.67 mg/325 mg) and Ultracet® upon singledose, oral administration in fasted humans.

DETAILED DESCRIPTION OF THE INVENTION Definitions and Conventions

The present technology provides compositions comprising aryl carboxylicacids chemically conjugated to hydrocodone (morphinan-6-one,4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs andcompositions of hydrocodone. In some embodiments, the chemical bondbetween these two moieties can be established by reacting the C-6 enoltautomer of hydrocodone with the activated carboxylic acid function ofan aryl carboxylic acid thereby creating an enol-ester conjugate.

The use of “opioid” is meant to include any drug that activates theopioid receptors found in the brain, spinal cord and gut. There are fourbroad classes of opioids: naturally occurring opium alkaloids, such asmorphine (the prototypical opioid) codeine, and thebaine; endogenousopioid peptides, such as endorphins; semi-synthetics such as heroine,oxycodone and hydrocodone that are produced by modifying natural opiumalkaloids (opiates) and have similar chemical structures; and puresynthetics such as fentanyl and methadone that are not produced fromopium and may have very different chemical structures than the opiumalkaloids. Additional examples of opioids are hydromorphone,oxymorphone, methadone, levorphanol, dihydrocodeine, meperidine,diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine,nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, andpharmaceutically acceptable salts thereof.

The use of “hydrocodone” is meant to include a semisynthetic narcoticanalgesic and antitussive prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is commonly used for therelief of moderate to moderately severe pain. Trade names includeAnexsia™, Hycodan™, Hycomine™, Lorcet™, Lortab™, Norco™, Tussionex™,Tylox™, and Vicodin™. Other salt forms of hydrocodone, such ashydrocodone bitartrate and hydrocodone polistirex, are encompassed bythe present technology.

The use of “prodrug” is meant to include pharmacologically inactivesubstances that are a modified form of a pharmacologically active drugto which it is converted in the body by, for example, enzymatic action,such as during first pass metabolism.

As used herein, the following conventional unit abbreviations and termsare used as follows: “pg” refers to picogram, “ng” refers to nanogram,“μg” refers to microgram, “mg” refers to milligram, “g” refers to gram,“kg” refers to kilogram, “mL” refers to milliliter, “h” refers to hourand “t” refers to time.

As used herein, the following conventional pharmacokinetic abbreviationsand terms are used as follows: “PK” refers to pharmacokinetics,“AUC_(0-t)” refers to area under the plasma concentration-time curve tothe last time with a concentration ≧LLOQ, “AUC_(inf)” refers to the areaunder the plasma concentration-time curve to infinity, “C_(max)” refersto the maximum plasma concentration, “T_(max)” refers to the time ofmaximum plasma concentration, “λz” refers to the elimination rateconstant and “t_(1/2)” refers to the elimination half-life.

As used herein, the following conventional statistical abbreviations andterms are used as follows: “LLOQ” refers to the validated lower limit ofthe bioanalytical method, “ANOVA” refers to Analysis of Variance and “p”refers to probability.

As used herein, “APAP” refers to acetaminophen.

As used herein, “LC/MS/MS” refers to liquid chromatography/massspectrometry/mass spectrometry.

Some embodiments of the present technology provide carboxylic acidsconjugated to hydrocodone, where the carboxylic acid group is directlyattached to the aryl moiety. Carboxylic acids directly attached to thearyl moiety include benzoates and heteroaryl carboxylic acids.

Some embodiments of the present technology provide at least oneconjugate of hydrocodone and at least one benzoic acid or benzoic acidderivative, a salt thereof, or a combination thereof. Benzoates arecommon in nature and include, for example but are not limited to,aminobenzoates (e.g., anthranilic acid analogs such as fenamates),aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acidanalogs).

The general structure of benzoic acid and benzoic acid derivatives ofthe present technology is:

where X, Y and Z can be independently any combination of H, O, S, NH or—(CH₂)_(x)—; R¹, R² and R³ can be independently any of the following: H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl, and o, p, q can be independently either 0 or 1; and x isan integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Suitable hydroxyobenzoic acids can be found in FIG. 1 and include, butare not limited to, benzoic acid, salicylic acid, acetylsalicylic acid(aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are notlimited to, anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids are shown in FIG. 3 and include, butare not limited to, 4-Aminosalicylic acid, 3-hydroxyanthranilic acid,3-methoxyanthranilic acid.

In some embodiments, the composition includes a benzoate conjugatecomprising at least one hydrocodone conjugated to at least one benzoicacid or benzoic acid derivative, salt thereof or combination thereof.

In some embodiments, the benzoates include numerous benzoic acidanalogs, benzoate derivatives with hydroxyl or amino groups or acombination of both. The hydroxyl and amino functions may be present intheir free form or capped with another chemical moiety, preferably butnot limited to methyl or acetyl groups. The phenyl ring may haveadditional substituents, but the total number of substituents can befour or less, three or less, or two or less.

In another embodiment, the prodrug or conjugate composition of thepresent technology is benzoate-hydrocodone, which has the structure:

In yet another embodiment, the present technology provides a prodrug orcomposition comprising at least one conjugate of hydrocodone and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof. The heteroaryl carboxylic acid can be selected fromformula II, formula III or formula IV where formula II, formula III andformula IV are:

For these formulas, X, Y and Z are independently selected from the groupconsisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ areindependently selected from the group consisting of H, alkyl, alkoxy,aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl,heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o,p, q are independently selected from 0 or 1; and x is an integer from 1to 10.

In some embodiments, the carboxy group of the aryl carboxylic acids canbe attached directly to the aromatic ring. The present technologyincludes both carbon-only aryl groups and aryl groups with heteroatoms(heteroaryl). The aryl or heteroaryl group which is connected directlyto the carboxyl function can be a 6-membered ring and contains no or oneheteroatom. In some embodiments, the additional substituted orunsubstituted aromatic or aliphatic rings can be fused to this6-membered aryl or heteroaryl moiety. In some embodiments, the arylcarboxylic acids may have only one free carboxylic acid group and thetotal number of phenyl substituents on the 6-membered ring should befour or less, for example, 4, 3, 2 or 1.

In some embodiments of the present technology, depending on theindividual aryl carboxylic acid that is connected to hydrocodone, theconjugate of hydrocodone can have a neutral, free acid, free base, orvarious pharmaceutically acceptable anionic or cationic salt forms orsalt mixtures with any ratio between positive and negative components.These salt forms include, but are not limited to: acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.

For the present technology, a suitable conjugate of hydrocodone includesnicotinate-hydrocodone, which has the following structure:

Some embodiments of the present technology provide a conjugate ofhydrocodone that is broken down in vivo either enzymatically orotherwise, releasing the active hydrocodone and the respective arylcarboxylic acid or metabolites thereof. The aryl carboxylic acids usedin the conjugates of the present technology are non-toxic at the givendosing levels and are preferably known drugs, natural products,metabolites, or GRAS (Generally Regarded As Safe) compounds (e.g.,preservatives, dyes, flavors, etc.) or non-toxic mimetics thereof.

Compounds, conjugates, products, prodrugs, compositions and methods ofthe present technology provide, for example, reduced potential foroverdose, reduced potential for abuse or addiction and/or improvehydrocodone's characteristics with regard to high toxicities orsuboptimal release profiles. Without wishing to be limited to the belowtheory, it is believed that the presently described and claimedtechnology provides overdose protection that may occur when thedescribed and claimed conjugates, compounds, compositions, prodrugs,and/or products are exposed to different enzymes and/or metabolicpathways by oral administration where the conjugates, compounds,compositions, products and/or prodrugs are exposed through the gut andfirst-pass metabolism as opposed to exposure to enzymes in thecirculation or mucosal membranes which limits the ability of thehydrocodone from being released from the conjugate. Therefore, abuseresistance and/or abuse deterrence is provided by limiting the “rush” or“high” available from the active hydrocodone released by the prodrug,product, composition, compound, and/or conjugate of the presenttechnology and limiting the effectiveness of alternative routes ofadministration.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. Again, not wanting to be bound by anyparticular theory, the bioavailability of the compositions of thepresent technology can be a result of the hydrolysis of the chemicallinkage (i.e., a covalent linkage) following oral administration. In atleast one embodiment of the present technology, release of hydrocodoneis reduced when the composition, compound, conjugate, product, orprodrug of the present technology is delivered, for example, byparenteral routes.

For example, in one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance followingthe crushing of the tablet, capsule or other oral dosage form. Incontrast, from parental non-conjugated (or “unconjugated”) forms ofhydrocodone, the hydrocodone is released immediately following crushingallowing the content of the crushed tablet to be used by injection orsnorting producing the “rush” effect sought by addicts.

In some embodiments of the present technology, the conjugates ofhydrocodone can be given orally to an animal or human patient, and, uponadministration, release the active hydrocodone by being hydrolyzed inthe body. Not to be bound by any particular theory, it is believed thatsince the aryl carboxylic acids are naturally occurring metabolites ormimetics thereof or pharmaceutically active compounds, these conjugatescan be easily recognized by physiological systems resulting inhydrolysis and release of hydrocodone. The conjugates themselves haveeither no or limited pharmacological activity as a conjugate andconsequently may follow a metabolic pathway that differs from the parentdrug.

In some embodiments of the present technology, the choice of a suitablearyl carboxylic acids (“ligands”) to conjugate to hydrocodone determinesthe release of hydrocodone into the systemic circulation and can becontrolled even when the conjugate is administered via routes other thanoral. In one embodiment, the modified hydrocodone would releasehydrocodone similar to free or unmodified hydrocodone. In anotherembodiment, the conjugated hydrocodone releases hydrocodone in acontrolled or sustained form. In some embodiments, this controlledrelease can alleviate certain side-effects and improve upon the safetyprofile of the parent drug. These side-effects may include, but are notlimited to, anxiety, bruising, constipation, decreased appetite,difficulty breathing, dizziness, drowsiness, dry throat, diarrhea,headache, nausea, stomach cramps, stomach pain, vomiting. In anotherembodiment, the conjugated hydrocodone would selectively allowhydrocodone to be metabolized to hydromorphone. In some embodiments,these conjugates can be used for pain relief, such as moderate to severepain relief.

Hydrocodone and other opioids are also highly addictive and prone tosubstance abuse. Recreational drug abuse of opioids is a common problemand usually begins with oral doses taken with the purpose of achievingeuphoria (“rush”, “high”). Over time the drug abuser often increases theoral dosages to attain more powerful “highs” or to compensate forheightened opioid tolerance. This behavior can escalate and result inexploring of other routes of administration such as intranasal(“snorting”) and intravenous (“shooting”).

In some embodiments of the present technology, the hydrocodone that isconjugated with a suitable aryl carboxylic acid ligand does not resultin rapid spikes in plasma concentrations after oral administration thatis sought by a potential drug abuser. In some embodiments, hydrocodonereleased from these conjugates has a delayed T_(max) and possibly lowerC_(max) than the unconjugated hydrocodone. Not to be bound by anyparticular theory, it is believed that the conjugates of the presenttechnology, when taken orally or by other non-oral routes, do notprovide the feeling of a “rush” even when taken at higher doses butstill maintain pain relief.

Additionally, in some embodiments, hydrocodone conjugated withappropriate ligands of the present technology is not hydrolyzedefficiently when administered via non-oral routes. As a result, theseconjugates do not generate high plasma or blood concentrations ofreleased hydrocodone when injected or snorted compared to freehydrocodone administered through these routes.

In some embodiments, the conjugates of the present technology, sincethey consist of covalently bound hydrocodone, are not able to bephysically manipulated to release the hydrocodone opioid from theconjugated hydrocodone by methods, for example, of grinding up orcrushing of solid forms. Further, the conjugates of the presenttechnology exhibits resistance to chemical hydrolysis under conditions apotential drug abuser may apply to “extract” the active portion of themolecule, for example, by boiling, or acidic or basic solution treatmentof the conjugate.

The compositions and prodrugs of the present technology can be oraldosage forms. These dosage forms include but are not limited to tablet,capsule, caplet, troche, lozenge, powder, suspension, syrup, solution ororal thin film (OTF). Preferred oral administration forms are capsule,tablet, solutions and OTF.

Solid dosage forms can include, but are not limited to, the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,fillers, flavors and colors, glidants, lubricants, preservatives,sorbents and sweeteners.

Oral formulations of the present technology can also be included in asolution or a suspension in an aqueous liquid or a non-aqueous liquid.The formulation can be an emulsion, such as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The oils can be administeredby adding the purified and sterilized liquids to a prepared enteralformula, which is then placed in the feeding tube of a patient who isunable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations with excipients designed to form a relatively soft,flavored, tablet dosage form that is intended to be chewed rather thanswallowed. Conventional tablet machinery and procedures, for example,direct compression and granulation, i.e., or slugging, beforecompression, can be utilized. Those individuals involved inpharmaceutical solid dosage form production are versed in the processesand the machinery used, as the chewable dosage form is a very commondosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing theformulation with excipients intended to add binding qualities todisintegration qualities. The mixture is either directly compressed orgranulated then compressed using methods and machinery known to those inthe industry. The resultant compressed tablet dosage units are thenpackaged according to market need, for example, in unit dose, rolls,bulk bottles, blister packs, etc.

The present technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited to, such materials include diluents,binders and adhesives, lubricants, plasticizers, disintegrants,colorants, bulking substances, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example,medically inert ingredients, e.g., solid and liquid diluents, such aslactose, dextrose, saccharose, cellulose, starch or calcium phosphatefor tablets or capsules, olive oil or ethyl oleate for soft capsules andwater or vegetable oil for suspensions or emulsions; lubricating agentssuch as silica, talc, stearic acid, magnesium or calcium stearate and/orpolyethylene glycols; gelling agents such as colloidal clays; thickeningagents such as gum tragacanth or sodium alginate, binding agents such asstarches, arabic gums, gelatin, methylcellulose, carboxymethylcelluloseor polyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulfates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

Current approved formulations of hydrocodone are combination therapiesof hydrocodone and one or more other non-narcotic active ingredientdepending on intended indication. Examples of these activepharmaceuticals include, but are not limited to, acetaminophen,phenylpropanolamine, homatropine, ibuprofen, aspirin, pheniramine,chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine andguaifenesin. The conjugated hydrocodone of the present technology can beformulated with one or a combination of these or other active substancesor as standalone active ingredient without any other actives.

Certain formulations of the compounds, products, compositions,conjugates and prodrugs of the current technology comprise Bz-HC.HCl,bulking agents and diluents, such as, for example, microcrystallinecellulose and crospovidone, disintegrants, such as, for example, starch1500 G, binders, such as, for example, povidone K30, lubricants, suchas, for example, stearic acid, and granulation solvents, such as, forexample, purified water. Such formulations of the current technology mayalso include additional pharmaceutical actives, such as, for example,acetaminophen.

The amounts and relative percentages of the different active andinactive components of the formulations of the current technology can bemodified, selected and adjusted in order to arrive at desirableformulations, dosages and dosage forms for therapeutic administration ofthe compounds, products, compositions, conjugates and prodrugs of thecurrent technology. One such oral dosage formulation of the presenttechnology is presented, for example, in Table 1.

TABLE 1 Strength (label claim) 6.67 mg/325 mg Component and Quality(Bz-HC•HCl/ Standard (and Grade, if Acetaminophen) applicable) Functionmg/tablet % w/w Bz-HC•HCl^(a,) Active 6.67 1.21 Acetaminophen USP Active325.0 59.09 Microcrystalline Cellulose Bulking Agent 154.78 28.16 NFCrospovidone NF Bulking 16.0 2.9 Agent/Diluent Starch 1500 G NFDisintegrant 20.0 3.64 Povidone K30 NF Binder 23.65 4.3 Stearic Acid NFLubricant 3.9 0.71 Purified water^(a) Granulation n/a n/a solvent^(a)Removed by evaporation during the process.

The conjugate compositions or prodrugs may be used in methods oftreating a patient having a disease, disorder or condition requiring ormediated by binding or inhibiting binding of an opioid to the opioidreceptors of the patient. Treatment comprises orally administering tothe patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone as described in the present technology. Theconjugate can exhibit a slower rate of release over time and AUC whencompared to an equivalent molar amount of unconjugated hydrocodone. Inother embodiments, at least one conjugate can exhibit less variabilityin the oral PK profile when compared to unconjugated hydrocodone.

In other embodiments, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC (area underthe curve) when compared to a molar equivalent amount of unconjugatedhydrocodone. In further embodiments, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent AUC whencompared to unconjugated hydrocodone but has a lower C_(max) (peakconcentration) in plasma or does not provide an equivalent C_(max) inplasma concentrations. In some aspects, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent C_(max)when compared to unconjugated hydrocodone.

Suitable diseases, disorders or conditions that can be treated by theprodrugs or compositions of the present technology are narcoticaddiction or drug addiction and/or acute or chronic pain.

Dosages for the conjugates of the present technology depend on theirmolecular weight and the respective weight-percentage of hydrocodone aspart of the whole conjugate, and therefore can be higher than thedosages of free hydrocodone. Dosages can be calculated based on thestrengths of dosages of hydrocodone bitartrate which range between 2.5mg and 15 mg per dose. Dose conversion from hydrocodone bitartrate tohydrocodone prodrug can be performed using the following formula:

dose(HC prodrug/conjugate)=[dose(HC bitartrate)×(molecular weight(HCprodrug/conjugate)/494.49)]/proportion of hydrocodone released fromprodrug/conjugate

HC: hydrocodone

Suitable dosages of the conjugated hydrocodone of the present technologyinclude, but are not limited to, formulations including from about 0.5mg or higher, alternatively from about 2.5 mg or higher, alternativelyfrom about 5.0 mg or higher, alternatively from about 7.5 mg or higher,alternatively from about 10 mg or higher, alternatively from about 20 mgor higher, alternatively from about 30 mg or higher, alternatively fromabout 40 mg or higher, alternatively from about 50 mg or higher,alternatively from about 60 mg or higher, alternatively from about 70 mgor higher, alternatively from about 80 mg or higher, alternatively fromabout 90 mg or higher, alternatively from about 100 mg or higher, andinclude any additional increments thereof, for example, 0.1, 0.2, 0.25,0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factorsthereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc.). The presenttechnology also includes dosage formulations including currentlyapproved formulations of hydrocodone (See FIG. 4), where the dosage canbe calculated using the above-noted formula determined by the amount ofhydrocodone bitartrate. The present technology provides for dosage formsformulated as a single therapy or as a combination therapy with otherAPI's (FIG. 4).

The conjugates of hydrocodone with derivatives of benzoic acid ornicotinic acid of the present technology have a number of advantagesincluding, but not limited to, a reduced patient variability of plasmaconcentrations of hydrocodone or hydromorphone when compared to freehydrocodone, reduced drug abuse potential, reduced risk of chemical orphysical manipulation resulting in full dosage of hydrocodone released,improved dosage forms through covalent linkage to carboxylic acids orderivatives thereof, increased or decreased metabolism of hydrocodone tohydromorphone and/or decreased side-effects other than drug abuse.

Hydrocodone is a narcotic analgesic, which acts as weak agonist atopioid receptors in the central nervous system (CNS). It primarilyaffects the μ (mu) receptor (OP3), but also exhibits agonist activity atthe δ (delta) receptor (OP1) and κ (kappa) receptor (OP2). Additionally,hydrocodone displays antitussive properties by suppressing the coughreflex in the medullary cough center of the brain.

Hydrocodone is used for the treatment of moderate to moderately severepain and for inhibition of cough (especially dry, nonproductive cough).The prodrugs of the present technology may be administered for therelief of pain or cough depression or for the treatment of any conditionthat may require the blocking of opioid receptors.

The present technology also provides a method of synthesis for thepreparation of the conjugated hydrocodone of the present technology. Inone embodiment, the synthesis of the present technology includes thesteps of:

-   -   1. Protection of the ligand, if necessary;    -   2. Activation of the ligand carboxylic acid group, if not        already in activated form;    -   3. Addition of the activated ligand to hydrocodone or vice versa        in the presence of base; and    -   4. Removal of ligand protecting groups, if applicable.

If the aryl carboxylic acid contains any additional reactive functionalgroups that may interfere with the coupling to hydrocodone, it may benecessary to first attach one or more protecting groups. Any suitableprotecting group may be used depending on the type of functional groupand reaction conditions. Some protecting group examples are: acetyl(Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM),p-methoxybenzyl ether (PMB), trimethylsilyl (TMS),tert.-butyldimethylsilyl (TBDPS), triisopropylsilyl (TIPS),carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz),tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation ofacetals or ketals from carbonyl functions may also be appropriate.

The carboxylic acid group of the ligands should be activated in order toreact with hydrocodone and to generate appreciable amounts of conjugate.This activation can be accomplished in numerous ways by a variety ofcoupling agents known to one skilled in the art. Examples of suchcoupling agents are: N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI),N,N′-diisopropylcarbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other aminium-based reagents. The aryl carboxylic acid can also beconverted to a suitable acyl halide, acyl azide or mixed anhydride.

A base may be required at any step in the synthetic scheme of an arylcarboxylic acid conjugate of hydrocodone. Suitable bases include but arenot limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine(DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide,lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g.,potassium tert.-butoxide), any alkali metal hydride (e.g., sodiumhydride), any alkali metal alkoxide (e.g., sodium methoxide),triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction in the syntheticscheme of an aryl carboxylic acid conjugate of hydrocodone include butare not limited to: acetone, acetonitrile, butanol, chloroform,dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, the prodrug is hydrophobic and thus poorly watersoluble. This results in a gel-like consistency or clumpy suspensionwhen the compound is mixed with water. Examples of these prodrugsinclude, but are not limited to, piperonylate-HC, 3-OH-4-MeO-Bz-HC,3-OH-Bz-HC and Gallate-HC. These prodrugs cannot be dosed intranasallyin rats due to their lack of water solubility. Not to be bound by anytheory, it is assumed that these compounds would also congeal or becomeclumpy when a human subject tries to inhale them intranasally(“snorting”). This property would not only make an attempt of intranasalabuse an unpleasant experience but would likely also prevent the prodrugfrom permeating the nose mucosa. As a consequence, these compoundsbecome ineffective for this route of administration.

The present technology provides pharmaceutical kits for the treatment orprevention of drug withdrawal symptoms or pain in a patient. The patientmay be a human or animal patient. Suitable human patients includepediatric patients, geriatric (elderly) patients, and normativepatients. The kit comprises a specific amount of the individual doses ina package containing a pharmaceutically effective amount of at least oneconjugate of hydrocodone of the present technology. The kit can furtherinclude instructions for use of the kit. The specified amount ofindividual doses may contain from about 1 to about 100 individualdosages, alternatively from about 1 to about 60 individual dosages,alternatively from about 10 to about 30 individual dosages, including,about 1, about 2, about 5, about 10, about 15, about 20, about 25, about30, about 35, about 40, about 45, about 50, about 55, about 60, about70, about 80, about 100, and include any additional increments thereof,for example, 1, 2, 5, 10 and multiplied factors thereof, (e.g., ×1, ×2,×2.5, ×5, ×10, ×100, etc.).

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

EXAMPLES Example 1: Chemical Stability of Benzoate and HeteroarylCarboxylate Conjugates of Hydrocodone

Exemplary conjugates of hydrocodone of the present technology andcontrol test conjugates not of the present technology were tested forchemical stability under conditions similar to what a potential drugabuser may use to “extract” the active portion of the molecule, forexample dissolved in water, hydrochloric acid or sodium bicarbonateeither at ambient temperature or 100° C. The conjugates were placed in asolution of water at either ambient temperature (about 20° C.) or in anoil bath at 100° C. for one hour and the amount of the conjugate thatwas hydrolyzed under these conditions was measured. Table 2 demonstratesthe results, showing that the conjugates did not release hydrocodone atambient temperature or when heated in water to 100° C. for one hour.

TABLE 2 water^(a) Compound ambient 100° C. 4-OH-Bz-HC 0% 0% 2-ABz-HC 0%0% 4-MeO-Bz-HC 0% 0%

Further, samples of conjugates of hydrocodone of the present technologywere tested and compared with samples of other conjugates not of thepresent technology of hydrocodone (Adipate-HC) for their hydrolysis tohydrocodone after dilution in 1 N hydrochloric acid (HCl) for 1 hour atambient temperature (˜20° C.) or in an oil bath at 100° C. Thepercentages indicate how much of the initial amount of conjugate washydrolyzed under these conditions. The results are shown in Table 3.

TABLE 3 %-release in 1N HCl^(a) Compound ambient 100° C. 4-OH-Bz-HC 0%30% 2-ABz-HC 0% 16% 3-OH-4-MeO-Bz-HC 0% 35% 2-OH-Bz-HC 3% 27% Adipate-HC13% 100%

Samples of each conjugate were dissolved in a solution of 5% NaHCO₃ forone hour at either ambient temperature (˜20° C.) or in an oil bath at100° C. The percentages indicate how much of the initial amount ofconjugate was hydrolyzed under these conditions as shown in Table 4 forthe conjugates of the present technology and comparison conjugates notof the present technology (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone (YYFFI-HC) orAdipiate-HC).

TABLE 4 %-release in 5% NaHCO₃ ^(a) Compound ambient 100° C. 4-OH-Bz-HC1% 23% 3-OH-4-MeO-Bz-HC 0% 36% YYFFI-HC 0% 70% Adipate-HC 3% 100%

Example 2: Oral PK Profiles of Conjugated Hydrocodone of the PresentTechnology

Oral PK curves were determined for benzoate-hydrocodone (Bz-HC), aprodrug of the present technology, as compared to two conjugates notwithin the scope of the present technology: YYFFI-HC and Diglycolate-HC.Rats were orally administered an amount of the conjugate equivalent to 2mg/kg of freebase hydrocodone and the plasma concentrations of releasedhydrocodone and of the active metabolite hydromorphone were measuredover time by LC/MS/MS. As shown in FIG. 5, the oral PK curves forreleased hydrocodone were somewhat similar for Bz-HC and YYFFI-HC, buthydrocodone plasma concentrations produced by Bz-HC were mostlysignificantly higher than hydrocodone concentrations generated byDiglycolate-HC (AUC and C_(max) for Bz-HC were approximately 40% and 50%higher, respectively). Additionally, Bz-HC created higher plasmaconcentrations of the more potent active metabolite hydromorphone (FIG.6) than both, YYFFI-HC (AUC and C_(max) for hydromorphone released fromBz-HC were approximately 60% and 80% higher, respectively) andDiglycolate-HC (AUC and C_(max) for hydromorphone released from Bz-HCwere approximately 55% and 180% higher, respectively). This suggeststhat all three compounds undergo a different metabolic pathway and thatBz-HC would have pain relieving effects potentially greater than eitherexample.

Example 3: Intranasal PK Profile of Conjugates of Hydrocodone

Conjugates of hydrocodone of the present technology were tested forabuse resistance capabilities by examining the efficiency of ahydrolysis when administered via routes other than oral. Rats wereintranasally treated with conjugate in an amount equivalent to 2 mg/kgof hydrocodone freebase and the concentration of released hydrocodoneand of the active metabolite hydromorphone in the plasma of the rat weremeasured over time by LC/MS/MS. Hydrocodone plasma concentrations weresignificantly lower for Bz-HC (AUC and C_(max) for hydromorphonereleased from Adipate-HC were approximately 280% and 60% higher,respectively) as shown in FIG. 7. Moreover, Bz-HC produced very lowplasma concentration of hydromorphone when compared to Adipate-HC (AUCand C_(max) for hydromorphone released from Adipate-HC wereapproximately 750% and 660% higher, respectively) as shown in FIG. 8.

Prodrugs of the present technology provide hydrocodone and hydromorphoneplasma concentrations that are significantly lower than respectiveplasma concentration for unbound Hydrocodone.BT or for other prodrugclasses when administered intranasally.

Example 4: Exemplary Intravenous PK Profiles of Conjugates of thePresent Technology

The conjugates of hydrocodone of the present technology are hydrophobic,for example, Bz-HC, Nicotinate-HC, 4-MeO-Bz-HC, Piperonylate-HC,4-OH-Bz-HC, Salicylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Gallate-HC.Therefore, these compounds cannot be administered intravenously at oralequivalent doses because they do not dissolve in a practical amount ofwater since injectable compounds must be completely in solution, becauseany solid particle may cause an embolism. The amount of water necessaryto dissolve a desirable amount of conjugate would make an injectionunfeasible and thus the present compositions and prodrugs haveanti-abuse potential as opposed to other hydrocodone conjugates that arewater soluble, such as Adipate-HC and Diglycolate-HC which can beadministered intravenously at oral equivalent doses.

Example 5: Comparison of Oral PK Profiles of Conjugates of Hydrocodone

The plasma concentrations of hydrocodone released from Bz-HC andNicotinate-HC were compared to plasma concentrations of hydrocodonegenerated by unconjugated Hydrocodone.BT after oral administration torats. Rats were treated with conjugate or unconjugated drug in an amountequivalent to 2 mg/kg of hydrocodone freebase and the plasmaconcentration of hydrocodone or hydromorphone was measured by LC/MS/MSas demonstrated in FIGS. 9 and 10 respectively. The oral plasmaconcentration of hydrocodone released from Bz-HC increased similarly tothe hydrocodone plasma concentrations observed with Hydrocodone.BT,until it reached C_(max) (C_(max) was approximately equal for bothcompounds). After T_(max), the hydrocodone plasma concentration forBz-HC decreased in a slower and more controlled fashion than forunconjugated Hydrocodone.BT (FIG. 9 and FIG. 10). Bz-HC had a higher AUC(AUC was approximately 25% higher, FIG. 9) when compared toHydrocodone.BT and similar results were observed for the plasmaconcentrations of the active metabolite hydromorphone (FIG. 10).

Nicotinate-HC, produced hydrocodone and hydromorphone plasmaconcentrations that were below the respective concentrations found forunconjugated Hydrocodone.BT. The corresponding AUC values, however, werewithin the range of bioequivalence for the same dose (based onhydrocodone freebase).

2-ABz-HC demonstrated a different release profile after oraladministration to rats than Bz-HC or the unconjugated drugHydrocodone.BT. Rats were treated with an amount equivalent to 2 mg/kgof hydrocodone freebase and the plasma concentration of hydrocodone orhydromorphone was measured by LC/MS/MS over time as shown in FIG. 11 orFIG. 12 respectively. 2-ABz-HC released hydrocodone very slowlyindicated by a gradual increase of plasma concentration followed by anattenuated decrease (FIG. 11). This resulted in a flattened PK curvewhen compared with Hydrocodone.BT (T_(max) for 2-ABz-HC wasapproximately four times longer, AUC and C_(max) were approximately 35%and 60% lower, respectively). Overall, the PK curve of hydromorphone wasalso flatter for 2-ABz-HC than for Hydrocodone.BT (FIG. 12) but did showa small initial spike (AUC and C_(max) for 2-ABz-HC were approximately25% and 50% lower, respectively).

Example 6: Determination of Variation in Plasma Concentrations ofBenzoate-Hydrocodone

To determine the variability of the plasma concentration of hydrocodone(HC) and hydromorphone (HM), the coefficient of variation (CV) wascalculated for individual animals that were dosed with an amountequivalent to 2 mg/kg of hydrocodone freebase of benzoate-hydrocodone orthe unconjugated hydrocodone bitartrate (BT) and the plasmaconcentrations of hydrocodone and hydromorphone were measured byLC/MS/MS over time. The CV was calculated by dividing the standarddeviation of plasma concentrations in individual animals by the meanplasma concentrations of all dosed animals for a given time point. The“average CV” is the mean CV for all time points, as shown in Table 5.

TABLE 5 Average CV^(a) Compound HC HM Bz-HC 46 41 Hydrocodone•BT 75 64

The lower average CV for Bz-HC indicates that this prodrug has lowerrelative variability in plasma concentrations of hydrocodone andhydromorphone across all dosed animals and time points than theunconjugated drug, hydrocodone bitartrate.

Example 7: Synthesis of Conjugates of Hydrocodone

Synthesis of Benzoate-Hydrocodone Freebase

To a solution of hydrocodone freebase (0.596 g, 1.99 mmol) intetrahydrofuran (25 mL) was added 1 M LiN(SiMe₃)₂ in tetrahydrofuran(5.98 mL). The resulting orange suspension was stirred at ambienttemperatures for 30 min. after which benzoate-succinic ester (1.25 g,5.98 mmol) was added. The resulting mixture was stirred overnight atambient temperatures and was quenched after 18 h by the addition of 100mL saturated ammonium chloride solution which was allowed to stir foranother 2 h. Ethyl acetate (100 mL) was added to the mixture and washedwith saturated ammonium chloride solution (3×100 mL) and water (1×100mL). Organic extracts were dried over anhydrous MgSO₄, solvent wasremoved and residue was taken up in 2-isopropanol (50 mL). Water wasadded until a solid formed. The resulting mixture was chilled, filteredand dried to obtain benzoate-hydrocodone freebase (0.333 g, 0.826 mmol,42% yield) as a dark brown solid. This synthesis is depicted in FIG.13A.

Synthesis of 2-Boc-Aminobenzoic Succinate:

2-Boc-aminobenzoic acid (2.56 g, 10.8 mmol) and N-hydroxysuccinimide(1.37 g, 11.88 mmol) were dissolved in 25 mL of THF. DCC (2.45 g, 11.88mmol) was added in one portion. The reaction was stirred overnight. Thesolid was filtered off and rinsed with acetone (2×10 mL). The filtratewas concentrated to dryness and dissolved in 100 mL of acetone. Theresulting precipitate (DCU) was filtered off and the filtrate wasconcentrated to give a solid, which was collected and rinsed withmethanol (3×4 mL) to yield 3.26 g (90%) of white product.

Synthesis of 2-Boc-Aminobenzoic Acid Ester of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-Boc-aminobenzoic succinate (1.50 g, 4.5 mmol) was added in oneportion. The reaction was stirred for 4 hours and subsequently quenchedwith 100 mL of sat. NH₄Cl. The mixture was stirred for 1 h. andextracted with 200 mL of ethyl acetate. The ethyl acetate layer waswashed with sat. NaHCO₃ (2×80 mL) and 5% brine (80 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (7% MeOH/CH₂Cl₂) to give 449 mg (58%) of anamorphous solid.

Synthesis of 2-Aminobenzoic Acid Ester of Hydrocodone DihydrochlorideSalt:

2-Boc-aminobenzoic acid ester of hydrocodone (259 mg, 0.5 mmol) wasstirred in 4 mL of 4 N HCl/dioxane for 4 h. The solvent was evaporatedto dryness and to the residue was added 5 mL of ethyl acetate. The solidwas collected and rinsed with ethyl acetate to give 207 mg (84%) ofproduct.

Synthesis of 2-MOM-Salicylic Succinate:

2-MOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2.23g, 19.36 mmol) were dissolved in 40 mL of THF. DCC (3.99 g, 19.36 mmol)was added in one portion. The reaction was stirred overnight. The solidwas filtered off and rinsed with acetone (2×10 mL). The filtrate wasconcentrated and the residue was recrystallized from 10 mL of methanolto give 2.60 g (53%) of a white solid.

Synthesis of 2-MOM-Salicylic Acid Ester of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-MOM-salicylic succinate (1.26 g, 4.5 mmol) was added in one portion.The reaction was stirred for 4 h. and subsequently quenched with 100 mLof sat. NH₄Cl. The mixture was stirred for 1 h. and extracted with 200mL of ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO₃(2×80 mL) and 5% brine (80 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (8% MeOH/CH₂Cl₂) to give 381 mg (58%) of a syrup.

Synthesis of Salicylic Acid Ester of Hydrocodone Hydrochloride Salt:

To 2-MOM-salicylic acid ester of hydrocodone (380 mg, 0.82 mmol) in 12mL of methanol was added 0.5 mL of conc. HCl (12 N). The reaction wasstirred for 6 hr. The solution was concentrated and residual water wasremoved by coevaporating with methanol (5×5 mL). The resulting residuewas dissolved in 1 mL of methanol followed by 20 mL of ethyl acetate.The cloudy mixture was evaporated to about 4 mL. The resulting solid wascollected and rinsed with ethyl acetate to yield 152 mg (41%) ofproduct.

Example 8: Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Rats

After oral administration of benzoate-hydrocodone (Bz-HC) to rats, PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. Rats were orally administered an amount of theconjugate equivalent to 2 mg/kg of freebase hydrocodone and the plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC/MS/MS. As shownin FIG. 14, the exposure to intact Bz-HC prodrug was much lower than theexposure to hydrocodone or hydromorphone (the AUC for intact Bz-HC wasapproximately 10% and 3% of the AUC values for hydrocodone andhydromorphone, respectively).

Example 9: Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Dogs

After oral administration of benzoate-hydrocodone (Bz-HC) orHydrocodone.BT to dogs, PK curves were determined for intact Bz-HC(Bz-HC arm only), hydrocodone, and the active metabolite hydromorphone.Dogs were orally administered an amount of Hydrocodone.BT or theconjugate equivalent to 2 mg/kg of freebase hydrocodone. The plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC/MS/MS.

A comparison of plasma concentrations of hydrocodone released from Bz-HCand Hydrocodone.BT is shown in FIG. 15. Overall, the plasmaconcentrations of hydrocodone generated by both compounds were quitesimilar. The systemic exposure to hydrocodone was somewhat reduced forBz-HC when compared to Hydrocodone.BT (the AUC value of hydrocodone forBz-HC was approximately 72% of the AUC value for Hydrocodone.BT). TheC_(max) value of hydrocodone for Bz-HC was approximately 92% of theC_(max) value for Hydrocodone.BT.

A comparison of the plasma concentrations of the active metabolite,hydromorphone, following oral administration of Bz-HC or Hydrocodone.BTis shown in FIG. 16. Systemic exposure and maximum plasma concentrationsof hydromorphone were similar for both compounds. The AUC and C_(max)values of hydromorphone for Bz-HC were approximately 103% and 109% ofthe respective values for Hydrocodone.BT

A comparison the plasma concentrations of intact Bz-HC and hydrocodonereleased from Bz-HC is shown in FIG. 17. Similar to the results seen inrats, the plasma concentrations of intact Bz-HC prodrug in dogs were lowwhen compared to the plasma concentrations of hydrocodone (the AUC valuefor intact Bz-HC was approximately 10% of the AUC value forhydrocodone).

Example 10: Intravenous PK Profiles of Conjugated Hydrocodone,Hydrocodone, and Hydromorphone in Rats

Bz-HC (0.30 mg/kg) was administered intravenously to rats. Due to itspoor water solubility (or solubility in PBS), 0.30 mg/kg was close tothe maximum dose that could be administered intravenously to rats. PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. The plasma concentrations of intact Bz-HC,released hydrocodone, and the active metabolite, hydromorphone, weremeasured over time by LC/MS/MS. The resulting PK curves are shown inFIG. 18.

Example 11: Oral PK Profiles of Hydrocodone and Hydromorphone FollowingVarious Dosages of Bz-HC in Rats

Bz-HC was orally administered to rats at dosages of 0.25, 0.50, 1.00,2.00, 3.00, or 4.00 mg/kg. The plasma concentrations of hydrocodone orhydromorphone were measured by LC/MS/MS, as demonstrated in FIGS. 19 and20, respectively. The exposures (AUC) to hydrocodone and hydromorphoneat doses of Bz-HC between 0.25 and 4.00 mg/kg were fairly linear. Therespective C_(max) values, however, were more variable, particularly forhydromorphone. The maximum plasma concentrations of hydromorphone didnot significantly change at doses above 2.00 mg/kg of Bz-HC.

Example 12: Tamper Resistance

In order to further evaluate the tamper-resistant properties of Bz-HC, awide variety of Bz-HC solvent extraction studies were performed.Bz-HC.HCl is soluble in various solvents, but dissolving Bz-HC.HCl insolution only yields the inactive prodrug in solution. The prodrug isnot cleaved and no hydrocodone becomes available. Bz-HC.HCl is much lesssoluble in water than the hydrocodone bitartrate that is used in certainhydrocodone bitartrate/APAP combination products. In addition, at thehuman physiological pH of 7.4 (blood), Bz-HC is highly insoluble. Wealso conducted a wide variety of Bz-HC solvent hydrolysis studies in ourown laboratories. As shown in Table 6 below, our studies indicate thatBz-HC is completely stable and will not hydrolyze in commonly availablesolvents, and is stable to conditions that hydrolyze other formulatedabuse-deterrent drugs (e.g., water and alcohol, with or withoutheating).

Solvent Hydrolysis: No Hydrocodone Release

TABLE 6 %-release of Hydrocodone Ambient Temperature at Boiling PointSolvent 0.5 h 1 h 4 h 0.5 h 1 h 4 h Water 0 0 0 0 0 0 Ethanol 0 0 0 0 00 Methanol 0 0 0 0 0 0 Acetone 0 0 0 0 0 0 Ethyl acetate 0 0 0 0 0 0Toluene 0 0 0 0 0 0 Xylene 0 0 0 0 0 0 Tetrahydrofuran 0 0 0 0 0 0Methyl ethyl 0 0 0 0 0 0 ketone Octane 0 0 0 0 0 0 Petrol ether 0 0 0 00 0

In addition, real-world studies that used typical drug abuser-accessiblesolvents and methodologies, as well as a simulated smoking study wereperformed. No hydrocodone release from the prodrug was observed in anyof these studies.

Finally, numerous enzymatic tampering studies were performed on Bz-HC,utilizing enzymes that included trypsin, pancreatin, pepsin and variousesterases, and no significant release of hydrocodone from the prodrugwas observed. Without being bound by theory, it is believed thatmetabolism of Bz-HC after oral administration that allows for the rapidrelease of therapeutic amounts of hydrocodone requires the combinationsand processes of the esterases and other enzymes functioning in theliving enterocytes and liver tissue inside the body.

These tamper-resistance studies, demonstrate that Bz-HC is verydifficult to tamper with and is stable under conditions that canpotentially defeat other abuse-deterrent technologies.

Description of Bioanalytical Methods Used in Examples 13-18

Validated LC/MS/MS methods were used to measure plasma concentrations ofBz-HC, hydrocodone, hydromorphone and acetaminophen (APAP). The lowerlimits of quantitation (LLOQ) for Bz-HC, hydrocodone, hydromorphone, andAPAP in plasma were 25 pg/mL, 250 pg/mL, 25 pg/mL, and 0.025 μg/mL,respectively for examples 14-18. For example 13, the lower limits ofquantitation (LLOQ) for Bz-HC, hydrocodone, hydromorphone were 0.5ng/mL.

Description of Pharmacokinetic and Statistical Analysis Conducted inExamples 13-18

Actual blood sampling collection times were used in all PK analyses. Perprotocol, times were used to calculate mean plasma concentrations forgraphical displays. Pharmacokinetic parameters for hydrocodone,hydromorphone, and APAP were calculated using standard equations fornon-compartmental analysis. Only plasma concentrations that were greaterthan the LLOQs for the respective assays were used in thepharmacokinetic analysis. Data were compared using the standard ANOVAmodel applied to the natural logarithms of the data.

Example 13: Bz-HC Human Pharmacokinetic Studies

Forty-two (42) healthy volunteers were enrolled in a single dosepharmacokinetic study. Subjects received a single dose of either 1capsule of Bz-HC.HCl capsule, 5 mg (22 volunteers), 2 capsules ofBz-HC.HCl, 5 mg (20 volunteers) or 1 tablet of Norco® (hydrocodonebitartrate/acetaminophen), 10 mg/325 mg (21 volunteers) orally. Allstudy doses were administered after a standard overnight fast(approximately 10 hours). The plasma concentrations of hydrocodone weremeasured by LC/MS/MS. The PK data and is summarized in Tables 7 and 8.These results show that at equimolar doses Bz-HC.HCl is bioequivalentand thus therapeutically equivalent to Norco® and similar immediaterelease hydrocodone combination products.

Single oral dose of 5 mg of Bz-HC.HCl summary:

TABLE 7 Parameter Hydrocodone Released from Bz-HC•HCl AUC_(0-24 h) 70.69h × ng/mL ± 17.39 h × ng/mL AUC_(inf) 79.37 h × ng/mL ± 18.67 h × ng/mLC_(max) 12.8 ng/mL ± 3.84 ng/mL T_(max) (mean) 1.866 h ± 0.901 h T_(max)(median) 1.5 h T_(max) (range) [0.5 h-4 h] t_(1/2) 3.79 h ± 0.88 h

Single oral dose of 10 mg of Bz-HC.HCl summary:

TABLE 8 Parameter Hydrocodone Released from Bz-HC•HCl AUC_(0-24 h) 165.4h × ng/mL ± 42.35 h × ng/mL AUC_(inf) 172.5 h × ng/mL ± 43.44 h × ng/mLC_(max) 24.7 ng/mL ± 6.43 ng/mL T_(max) (mean) 1.700 h ± 0.880 h T_(max)(median) 1.5 h T_(max) (range) [0.5 h-4 h] t_(1/2) 4.36 h ± 0.81 h

Example 14: Bz-HC.HCl/APAP Single Dose Human Pharmacokinetic Studies

A study, was conducted to determine the rate and extent of absorption ofhydrocodone, hydromorphone, and acetaminophen (APAP) from Bz-HC.HCl/APAPtablets (1×6.67 mg/325 mg) relative to Norco® tablets (1×7.5 mg/325 mg)when administered to healthy subjects under fasted conditions.

This was an open-label, single-dose, randomized, 2-treatment, 2-period,2-sequence, crossover bioavailability study in which 30 healthy adultsubjects were to be enrolled with the goal of completing 24. Subjectsreceived two single-dose treatments according to a randomizationschedule. Each treatment was separated by at least a 7-day washoutperiod. All study doses were administered after a standard overnightfast (approximately 10 hours). Each dose was administered along withapproximately 240 mL (8 fl. oz.) of room temperature tap water. No foodwas allowed until 4 hours after dose administration. Except for the 240mL of room temperature tap water provided with the dose, no water wasconsumed for 1 hour prior through 1 hour after dosing.

Blood samples for pharmacokinetic analysis were collected prior to andup to 24 hours after each dose.

A total of 30 subjects were enrolled and 23 subjects completed bothperiods of the study to comprise the pharmacokinetic (PK) analysispopulation.

A summary of the PK data for hydrocodone, hydromorphone andacetaminophen is presented in Tables 9, 10, and 11. PK curves of the ofthe mean±standard error plasma concentrations of hydrocodone,hydromorphone and acetaminophen are presented in FIGS. 24, 25, and 26,respectively.

HYDROCODONE Summary: single dose; Bz-HC.HCl/APAP tablet, 6.67 mg/325 mg;oral; fasted

TABLE 9 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-24 h)112,088 h × pg/mL ± 28,774 h × pg/mL AUC_(inf) 115,773 h × pg/mL ±29,099 h × pg/mL C_(max) 16,859 pg/mL ± 4,153 pg/mL T_(max) (mean) 1.351h ± 0.535 h T_(max) (median) 1.25 h T_(max) (range) [0.5 h-3 h] t_(1/2)4.214 h ± 0.574 hHYDROMORPHONE Summary: single dose; Bz-HC.HCl/APAP tablet, 6.67 mg/325mg; oral; fasted

TABLE 10 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-24 h) 1,453 h × pg/mL ± 900 h × pg/mL AUC_(inf) 1,702 h × pg/mL ±1,215 h × pg/mL (only N = 14) C_(max) 225 pg/mL ± 120 pg/mL T_(max)(mean) 1.065 h ± 1.156 h T_(max) (median) 0.5 h T_(max) (range) [0.5 h-6h] t_(1/2) 8.282 h ± 6.327 h (only N = 14)ACETAMINOPHEN (APAP) Summary: single dose; Bz-HC.HCl/APAP tablet, 6.67mg/325 mg; oral; fasted

TABLE 11 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-24 h) 16.388h × μg/mL ± 3.987 h × μg/mL AUC_(inf) 17.220 h × μg/mL ± 3.696 h × μg/mLC_(max) 4.067 μg/mL ± 1.319 μg/mL T_(max) (mean) 0.717 h ± 0.394 hT_(max) (median) 0.5 h T_(max) (range) [0.5 h-2 h] t_(1/2) 4.934 h ±0.977 h

Example 15: Bz-HC.HCl/APAP Steady State Human Pharmacokinetic Studies

A study was conducted to assess the pharmacokinetics of Bz-HC,hydrocodone, hydromorphone, and acetaminophen (APAP) after single andmultiple doses of Bz-HC.HCl/APAP tablets (2×6.67 mg/325 mg) under fastedconditions and the systemic exposure to Bz-HC after administration ofmultiple doses of Bz-HC.HCl/APAP tablets (2×6.67 mg/325 mg) with a totaldaily dose of 12 tablets based on the maximum daily APAP dose of 4grams.

This was a single-period, single- and multiple-dose study in which 26healthy adult subjects were to be enrolled with the goal of completing20. After completing an overnight fast (10 hours), subjects received asingle dose (Dose 1, Day 1) of 2 Bz-HC.HCl/APAP tablets to evaluatesingle-dose pharmacokinetics. Twenty-four (24) hours after the firstdose (Day 2), subjects entered the multi-dose portion of the study andreceived 2 Bz-HC.HCl/APAP tablets (Dose 2 through Dose 14) every 4 hoursfor a total of 14 doses in a confined setting.

Blood samples for pharmacokinetic analysis were collected prior to andup to 24 hours after dose 1 (Day 1) and Dose 14 (Day 4). In addition, toconfirm that steady-state was achieved, blood samples were collectedprior to Doses 4 and 6 on Day 2, and prior to Doses 8, 10, and 12 on Day3. A total of 26 subjects were enrolled and 24 subjects completed thestudy. The 24 subjects that completed the study comprised thepharmacokinetic (PK) analysis population.

A summary of the PK data for hydrocodone single dose, multiple dose andsteady state is presented in Tables 12, 13, and 14, respectively. Asummary of the PK data for hydromorphone single dose and multiple doseis presented in Tables 15 and 16, respectively. A summary of the PK datafor acetaminophen single dose, multiple dose and steady state ispresented in Tables 17, 18, and 19. PK curves of the of themean±standard error plasma concentrations of hydrocodone, hydromorphoneand acetaminophen are present in FIGS. 27, 28, and 29, respectively.These results demonstrate that the PK of hydrocodone and acetaminophenare linear and predictable after administration of single and multipledoses of Bz-HC.HCl.

HYDROCODONE Single Doses: single oral dose of Bz-HC.HCl/APAP tablets,13.34 mg/650 mg

TABLE 12 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-4 h)92,940 h × pg/mL ± 20,158 h × pg/mL AUC_(0-24 h) 212,948 h × pg/mL ±52,803 h × pg/mL AUC_(inf) 219,357 h × pg/mL ± 57,283 h × pg/mL C_(max)33,946 pg/mL ± 8,407 pg/mL T_(max) (mean) 1.173 h ± 0.709 h T_(max)(median) 1 h T_(max) (range) [0.5 h-4 h] t_(1/2) 4.448 h ± 0.590 hHYDROCODONE Multiple Doses: post-dose at steady-state, oral dose ofBz-HC.HCl/APAP tablets, 13.34 mg/650 mg

TABLE 13 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-4 h)195,074 h × pg/mL ± 47,655 h × pg/mL AUC_(0-24 h) 432,752 h × pg/mL ±118,669 h × pg/mL C_(max) 62,788 pg/mL ± 14,751 pg/mL T_(max) (mean)1.295 h ± 0.361 h T_(max) (median) 1.25 h T_(max) (range) [0.5 h-2 h]t_(1/2) 4.874 h ± 0.629 h

HYDROCODONE Steady-state:

TABLE 14 steady-state reached >24 h with Q4H dosing (after Dose 6)C_(max) ratio (single dose vs. steady-state): 1.85 AUC_(0-4 h) ratio(single dose vs. steady-state): 2.10 AUC_(0-24 h) ratio (single dose vs.steady-state): 2.03HYDROMORPHONE Single Doses: single oral dose of Bz-HC.HCl/APAP tablets,13.34 mg/650 mg

TABLE 15 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-4 h) 888 h × pg/mL ± 431 h × pg/mL AUC_(0-24 h) 2,148 h × pg/mL ±1,197 h × pg/mL AUC_(inf) 2,418 h × pg/mL ± 1,249 h × pg/mL (only N =11) C_(max) 372 pg/mL ± 184 pg/mL T_(max) (mean) 0.776 h ± 0.350 hT_(max) (median) 0.5 h T_(max) (range) [0.5 h-1.5 h] t_(1/2) 8.896 h ±3.892 h (only N = 11)HYDROMORPHONE Multiple Doses: post-dose at steady-state, oral dose ofBz-HC.HCl/APAP tablets, 13.34 mg/650 mg

TABLE 16 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-4 h) 1,727 h × pg/mL ± 770 h × pg/mL AUC_(0-24 h) 5,645 h × pg/mL± 2,525 h × pg/mL C_(max) 548 pg/mL ± 232 pg/mL T_(max) (mean) 0.919 h ±0.568 h T_(max) (median) 0.773 h T_(max) (range) [0.5 h-3 h] t_(1/2)13.306 h ± 3.602 h (only N = 9)ACETAMINOPHEN SINGLE Doses: single oral dose of Bz-HC.HCl/APAP tablets,13.34 mg/650 mg

TABLE 17 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-4 h) 17.622h × μg/mL ± 4.247 h × μg/mL AUC_(0-24 h) 30.526 h × μg/mL ± 12.736 h ×μg/mL AUC_(inf) 28.945 h × μg/mL ± 7.069 h × μg/mL C_(max) 7.951 μg/mL ±2.157 μg/mL T_(max) (mean) 0.797 h ± 0.567 h T_(max) (median) 0.5 hT_(max) (range) [0.5 h-3 h] t_(1/2) 4.787 h ± 1.210 hACETAMINOPHEN Multiple Doses: post-dose at steady-state, oral dose ofBz-HC.HCl/APAP tablets, 13.34 mg/650 mg

TABLE 18 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-4 h) 29.820h × μg/mL ± 6.186 h × μg/mL AUC_(0-24 h) 54.997 h × μg/mL ± 13.570 h ×μg/mL C_(max) 11.033 μg/mL ± 2.344 μg/mL T_(max) (mean) 0.908 h ± 0.380h T_(max) (median) 1 h T_(max) (range) [0.5 h-1.5 h] t_(1/2) 6.840 h ±2.415 h

ACETAMINOPHEN Steady-state:

TABLE 19 steady-state reached between 24 h and 36 h with Q4H dosingC_(max) ratio (single dose vs. steady-state): 1.38 AUC_(0-4 h) ratio(single dose vs. steady-state): 1.69 AUC_(0-24 h) ratio (single dose vs.steady-state): 1.80

Example 16: Bz-HC.HCl/APAP Human Pharmacokinetic Effect of Food Studies

A study was conducted to assess the effect of food on thebioavailability and pharmacokinetics of hydrocodone and acetaminophen(APAP) from Bz-HC.HCl/APAP tablets, 6.67 mg/325 mg and to assess therelative bioavailability of Bz-HC.HCl/APAP tablet, 6.67 mg/325 mg andNorco® tablet, 7.5 mg/325 mg under fed conditions in healthy volunteers.

This was a single-dose, randomized, 3-treatment, 3-period, 6-sequence,crossover study in which 42 healthy adult subjects were to be enrolledwith the goal of completing 30. Subjects received single-dose treatmentsaccording to a randomization schedule. The fed treatments included asingle dose of Bz-HC.HCl/APAP, 6.67 mg/325 mg and a single dose ofNorco®, 7.5 mg/325 mg, administered under fed conditions while thefasted treatment included Bz-HC.HCl/APAP, 6.67 mg/325 mg, administeredunder fasted conditions.

Each treatment period was separated by at least a 7-day washout period.Fasted doses were administered after a standard overnight fast(approximately 10 hours) and fed doses were administered 30 minutesafter beginning to ingest a standard meal. Each dose was administeredalong with approximately 240 mL (8 fl. oz.) of room temperature tapwater. No food was allowed until 4 hours after dose administration.Except for the 240 mL of room temperature tap water provided with thedose, no water was consumed for 1 hour prior through 1 hour afterdosing.

Blood samples for pharmacokinetic analysis were collected prior to andup to 24 hours after each dose.

A total of 42 subjects were enrolled. The pharmacokinetic (PK) analysispopulation was comprised of 40 subjects for the fed treatments (39 forAPAP) and 38 subjects for the fasted treatment.

A summary of the PK data for hydrocodone fasted, fed and fed vs. fastedis presented in Tables 20, 21, and 22, respectively. A summary of the PKdata for hydromorphone fasted, fed and fed vs. fasted is presented inTables 23, 24, and 25, respectively. A summary of the PK data foracetaminophen fasted, fed and fed vs. fasted is presented in Tables 26,27, and 28, respectively. PK curves of the of the mean±standard errorplasma concentrations of hydrocodone, hydromorphone and acetaminophenunder fed and fasted conditions are presented in FIGS. 32, 33, and 34,respectively. These results demonstrate that Bz-HC.HCl/APAP (6.67 mg/325mg) shows no clinically relevant food effect.

HYDROCODONE Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fasted

TABLE 20 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-24 h)121,404 h × pg/mL ± 35,183 h × pg/mL AUC_(inf) 125,729 h × pg/mL ±36,783 h × pg/mL C_(max) 19,175 pg/mL ± 4,840 pg/mL T_(max) (mean) 1.408h ± 0.602 h T_(max) (median) 1.25 h T_(max) (range) [0.5 h-3 h] t_(1/2)4.325 h ± 0.669 hHYDROCODONE Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fed

TABLE 21 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-24 h)125,798 h × pg/mL ± 26,900 h × pg/mL AUC_(inf) 130,905 h × pg/mL ±29,451 h × pg/mL C_(max) 16,044 pg/mL ± 3,608 pg/mL T_(max) (mean) 2.502h ± 0.955 h T_(max) (median) 2.5 h T_(max) (range) [0.5 h-4 h] t_(1/2)4.530 h ± 0.700 hHYDROCODONE Fed vs. Fasted:

TABLE 22 C_(max) decreased with food by 16.3% (mean to mean), from −48%to 37% AUC_(0-24 h) increased with food by 3.6% (mean to mean), from−37% to 77% AUC_(inf) increased with food by 4.1% (men to mean), from−38% to 80% T_(max) (mean) change from T_(max) (median) increased withfood from 1.25 h T_(max) (range) increased with food from [0.5 h-3 h](fasted) to [0.5 h-4 h] (fed)HYDROMORPHONE Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fasted

TABLE 23 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-24 h) 1,521 h × pg/mL ± 915 h × pg/mL AUC_(inf) 2,229 h × pg/mL ±1,272 h × pg/mL (only N = 17) C_(max) 235 pg/mL ± 130 pg/mL T_(max)(mean) 0.994 h ± 0.597 h T_(max) (median) 1 h T_(max) (range) [0.5 h-3h] t_(1/2) 11.185 h ± 4.411 h (only N = 17)HYDROMORPHONE Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fed

TABLE 24 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-24 h) 1,806 h × pg/mL ± 1,141 h × pg/mL AUC_(inf) 2,562 h × pg/mL± 1,463 h × pg/mL (only N = 30) C_(max) 194 pg/mL ± 113 pg/mL T_(max)(mean) 2.358 h ± 1.158 h T_(max) (median) 2 h T_(max) (range) [0.5 h-6h] t_(1/2) 12.182 h ± 5.447 h (only N = 30)HYDROMORPHONE Fed vs. Fasted:

TABLE 25 C_(max) decreased with food by 17.5% (mean to mean), from −78%to 193% AUC_(0-24 h) increased with food by 18.7% (mean to mean), from−73% to 386% T_(max) (mean) change from −25% to 786% T_(max) (median)increased with food from 1 h (fasted) to 2 h (fed) T_(max) (range)increased with food from [0.5 h-3 h] (fasted) to [0.5 h-6 h] (fed)ACETAMINOPHEN Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fasted

TABLE 26 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-24 h) 14.640h × μg/mL ± 4.424 h × μg/mL AUC_(inf) 14.683 h × μg/mL ± 3.867 h × μg/mLC_(max) 4.048 μg/mL ± 1.300 μg/mL T_(max) (mean) 1.054 h ± 0.708 hT_(max) (median) 1 h T_(max) (range) [0.5 h-3 h] t_(1/2) 4.781 h ± 1.303hACETAMINOPHEN Food Effect: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP, fed

TABLE 27 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-24 h) 14.497h × μg/mL ± 3.414 h × μg/mL AUC_(inf) 15.031 h × μg/mL ± 3.533 h × μg/mLC_(max) 3.344 μg/mL ± 1.011 μg/mL T_(max) (mean) 1.547 h ± 0.871 hT_(max) (median) 1.5 h T_(max) (range) [0.5 h-4 h] t_(1/2) 5.636 h ±1.577 hACETAMINOPHEN Fed vs. Fasted:

TABLE 28 C_(max) decreased with food by 17.4% (mean to mean), from −56%to 58% AUC_(0-24 h) decreased with food by 1.0% (mean to mean), from−42% to 75% AUC_(inf) increased with food by 2.4% (mean to mean), from−38% to 72% T_(max) (mean) change from −62% to 598% T_(max) (median)increased with food from 1 h (fasted) to 1.5 h (fed) T_(max) (range)increased with food from [0.5 h-3 h] (fasted) to [0.5 h-4 h] (fed)

Example 17: Bz-HC.HCl/APAP Single Dose Human Pharmacokinetic Studies

An additional study was conducted to further investigate the rate andextent of absorption of hydrocodone and hydromorphone fromBz-HC.HCl/APAP tablets (1×6.67 mg/325 mg) when administered to healthysubjects under fasted conditions.

This was a single-dose, randomized, 2-treatment, 2-period, 2-sequence,crossover study in which 30 healthy adult subjects were to be enrolledwith the goal of completing 26. Subjects received 2 single-dosetreatments according to a randomization schedule. The treatment includedwere Bz-HC.HCl/APAP, 6.67 mg/325 mg and Vicoprofen® (hydrocodonebitartrate/ibuprofen), 7.5 mg/200 mg, administered under fastedconditions.

Each treatment period was separated by at least a 7-day washout period.Each dose was administered after a standard overnight fast(approximately 10 hours) with approximately 240 mL (8 fl. oz.) of roomtemperature tap water. No food was allowed until 4 hours after doseadministration. Except for the 240 mL of room temperature tap waterprovided with the dose, no water was consumed for 1 hour prior through 1hour after dosing.

Blood samples for pharmacokinetic analysis were collected prior to andup to 24 hours after each dose.

A total of 30 subjects were enrolled. Twenty-eight (28) subjectscompleted both study periods. The pharmacokinetic (PK) analysispopulation was comprised of 28 subjects.

A summary of the PK data for hydrocodone and hydromorphone is presentedin Tables 29 and 30, respectively. PK curves of the of the mean±standarderror plasma concentrations of hydrocodone and hydromorphone arepresented in FIGS. 36 and 37, respectively.

HYDROCODONE summary: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP

TABLE 29 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-24 h)132,618 h × pg/mL ± 34,198 h × pg/mL AUC_(inf) 136,499 h × pg/mL ±34,899 h × pg/mL C_(max) 21,061 pg/mL ± 4,426 pg/mL T_(max) (mean) 1.241h ± 0.394 h T_(max) (median) 1.00 h T_(max) (range) [0.5 h-2 h] t_(1/2)4.190 h ± 0.638 hHYDROMORPHONE summary: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP

TABLE 30 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-24 h) 1,741 h × pg/mL ± 896 h × pg/mL AUC_(inf) 2,269 h × pg/mL ±1,541 h × pg/mL (only N = 4) C_(max) 246 pg/mL ± 98 pg/mL T_(max) (mean)0.964 h ± 0.434 h T_(max) (median) 1.00 h T_(max) (range) [0.5 h-2 h]t_(1/2) 8.791 h ± 4.827 h

Example 18: Bz-HC.HCl/APAP Single Dose Human Pharmacokinetic Studies

An additional study was conducted to further analyze the rate and extentof absorption of hydrocodone, and hydromorphone, and acetaminophen(APAP) from Bz-HC.HCl/APAP tablets (1×6.67 mg/325 mg) when administeredto healthy subjects under fasted conditions.

This was a single-dose, randomized, 2-treatment, 2-period, 2-sequence,crossover study in which 26 healthy adult subjects were to be enrolledwith the goal of completing 20. Subjects received 2 single-dosetreatments according to a randomization schedule. The treatmentsincluded were Bz-HC.HCl/APAP, 6.67 mg/325 mg and Ultracet®(tramadol/acetaminophen), 37.5 mg/325 mg, administered under fastedconditions.

Each treatment period was separated by at least a 7-day washout period.Each dose was administered after a standard overnight fast(approximately 10 hours) with approximately 240 mL (8 fl. oz.) of roomtemperature tap water. No food was allowed until 4 hours after doseadministration. Except for the 240 mL of room temperature tap waterprovided with the dose, no water was consumed for 1 hour prior through 1hour after dosing.

Blood samples for pharmacokinetic analysis were collected prior to andup to 36 hours after each dose.

A total of 30 subjects were enrolled. Twenty-seven (27) subjectscompleted both study periods. The pharmacokinetic (PK) analysispopulation was comprised of 27 subjects.

A summary of the PK data for hydrocodone, hydromorphone, andacetaminophen is presented in Tables 31, 32, and 33, respectively. PKcurves of the of the mean±standard error plasma concentrations ofhydrocodone, hydromorphone and acetaminophen are presented in FIGS. 38,39, and 40, respectively.

HYDROCODONE summary: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP

TABLE 31 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-36 h)124,102 h × pg/mL ± 30,541 h × pg/mL AUC_(inf) 128,085 h × pg/mL ±30,784 h × pg/mL C_(max) 19,278 pg/mL ± 5,462 pg/mL T_(max) (mean) 1.595h ± 0.922 h T_(max) (median) 1.25 h T_(max) (range) [0.5 h-4 h] t_(1/2)4.347 h ± 0.681 hHYDROMORPHONE summary: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP

TABLE 32 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-36 h) 1,644 h × pg/mL ± 1,012 h × pg/mL AUC_(inf) not availableC_(max) 224 pg/mL ± 137 pg/mL T_(max) (mean) 1.185 h ± 0.798 h T_(max)(median) 1.00 h T_(max) (range) [0.5 h-4 h] t_(1/2) not availableACETAMINOPHEN summary: single oral dose of 6.67 mg/325 mg ofBz-HC.HCl/APAP

TABLE 33 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-36 h) 15.138h × μg/mL ± 4.480 h × μg/mL AUC_(inf) 15.472 h × μg/mL ± 4.572 h × μg/mLC_(max) 3.810 μg/mL ± 1.301 μg/mL T_(max) (mean) 1.243 h ± 1.064 hT_(max) (median) 1.00 h T_(max) (range) [0.5 h-4 h] t_(1/2) 5.269 h ±1.856 h

Example 19: Bz-HC.HCl/APAP Single Dose Human Pharmacokinetic Studies

The dose-dependent ranges of the PK parameters obtained in single dosestudies conducted with oral formulations containing Bz-HC.HCl at dosesfrom 5 mg to 13.34 mg in fasted, healthy subjects are summarized forhydrocodone, hydromorphone and APAP, as applicable, in Tables 34, 35,and 36, respectively. The ranges of the PK parameters obtained in singleoral dose studies conducted with Bz-HC.HCl/APAP tablets, 6.67 mg/325 mgin fasted, healthy subjects are summarized hydrocodone, hydromorphoneand APAP, as applicable, in Tables 37, 38 and 39, respectively.

HYDROCODONE summary: single oral dose from 5 mg to 13.34 mg ofBz-HC.HCl, fasted

TABLE 34 Hydrocodone Parameter Released from Bz-HC•HCl or Bz-HC•HCl/APAPAUC_(0-24 h) 70.69 h × ng/mL ± 17.39 h × ng/mL to 212.95 h × ng/mL ±52.80 h × ng/mL AUC_(inf) 79.37 h × ng/mL ± 18.67 h × ng/mL to 219.36 h× ng/mL ± 57.28 h × ng/mL C_(max) 12.8 ng/mL ± 3.84 ng/mL to 33.95 ng/mL± 8.41 ng/mL T_(max) (mean) 1.173 h ± 0.709 h to 1.866 h ± 0.901 hT_(max) (median) 1 h to 1.5 h T_(max) (range) [0.5 h-4 h] t_(1/2) 3.79 h± 0.88 h to 4.448 h ± 0.590 hHYDROMORPHONE summary: single oral dose from 6.67 mg to 13.34 mg ofBz-HC.HCl, fasted

TABLE 35 Hydromorphone Released from Bz-HC•HCl or ParameterBz-HC•HCl/APAP AUC_(0-24 h) 1,453 h × pg/mL ± 900 h × pg/mL to 2,148 h ×pg/mL ± 1,197 h × pg/mL C_(max) 194 pg/mL ± 113 pg/mL to 372 pg/mL ± 184pg/mL T_(max) (mean) 0.776 h ± 0.350 h to 1.065 h ± 1.156 h T_(max)(median) 0.5 h to 1 h T_(max) (range) [0.5 h-6 h]ACETAMINOPHEN summary: single oral dose from 6.67 mg to 13.34 mg ofBz-HC.HCl, fasted

TABLE 36 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-24 h) 14.640h × μg/mL ± 4.424 h × μg/mL to 30.526 h × μg/mL ± 12.736 h × μg/mLAUC_(inf) 14.683 h × μg/mL ± 3.867 h × μg/mL to 28.945 h × μg/mL ± 7.069h × μg/mL C_(max) 4.048 μg/mL ± 1.300 μg/mL to 7.951 μg/mL ± 2.157 μg/mLT_(max) (mean) 0.717 h ± 0.394 h to 1.054 h ± 0.708 h T_(max) (median)0.5 h to 1 h T_(max) (range) [0.5 h-3 h] t_(1/2) 4.781 h ± 1.303 h to4.934 h ± 0.977 hHYDROCODONE summary: single oral dose of Bz-HC.HCl/APAP, 6.67 mg/325 mg,fasted

TABLE 37 Parameter Hydrocodone Released from Bz-HC•HCl/APAP AUC_(0-24 h)112.09 h × ng/mL ± 28.77 h × ng/mL to 132.62 h × ng/mL ± 34.20 h × ng/mLAUC_(inf) 115.77 h × ng/mL ± 29.10 h × ng/mL to 136.50 h × ng/mL ± 34.90h × ng/mL C_(max) 16.86 ng/mL ± 4.15 ng/mL to 21.06 ng/mL ± 4.43 ng/mLT_(max) (mean) 1.241 h ± 0.394 h to 1.595 h ± 0.922 h T_(max) (median) 1h to 1.25 h T_(max) (range) [0.5 h-4 h] t_(1/2) 4.190 h ± 0.638 h to4.347 h ± 0.681 hHYDROMORPHONE summary: single oral dose of Bz-HC.HCl/APAP, 6.67 mg/325mg, fasted

TABLE 38 Parameter Hydromorphone Released from Bz-HC•HCl/APAPAUC_(0-24 h) 1,453 h × pg/mL ± 900 h × pg/mL to 1,741 h × pg/mL ± 896 h× pg/mL C_(max) 224 pg/mL ± 137 pg/mL to 246 pg/mL ± 98 pg/mL T_(max)(mean) 0.964 h ± 0.434 h to 1.185 h ± 0.798 h T_(max) (median) 0.5 h to1 h T_(max) (range) [0.5 h-6 h]ACETAMINOPHEN summary: single oral dose of Bz-HC.HCl/APAP, 6.67 mg/325mg, fasted

TABLE 39 Parameter APAP Released from Bz-HC•HCl/APAP AUC_(0-24 h) 16.388h × μg/mL ± 3.987 h × μg/mL to 14.640 h × μg/mL ± 4.424 h × μg/mLAUC_(inf) 17.220 h × μg/mL ± 3.696 h × μg/mL to 14.683 h × μg/mL ± 3.867h × μg/mL C_(max) 3.810 μg/mL ± 1.301 μg/mL to 4.067 μg/mL ± 1.319 μg/mLT_(max) (mean) 0.717 h ± 0.394 h to 1.243 h ± 1.064 h T_(max) (median)0.5 h to 1 h T_(max) (range) [0.5 h-4 h] t_(1/2) 4.781 h ± 1.303 h to5.269 h ± 1.856 h

Example 20: Oral Bz-HC Pharmacokinetic Studies

LC/MS/MS analyses were performed in order to attempt to measure intactBz-HC concentrations in the plasma samples obtained from any of theblood samples described above in Examples 13-18. However, all plasmaconcentrations of intact Bz-HC were <LLOQ (25 pg/mL) and no PK analysescould be performed

Example 21: Bz-HC/APAP Single Dose Human Pharmacokinetic Studies

This was a randomized, double-blind, placebo-controlled, single-dose,seven-way crossover study to determine the relative bioavailability,abuse potential, and safety of equivalent oral doses compared withhydrocodone/acetaminophen in which a total of 151 opioid experiencednondependent subjects enrolled with 59 subjects completing the study.Subjects received 12 tablets of 80.04 mg/3,900 mg Bz-HC.HCl/APAP, 8tablets of 53.36 mg/2,600 mg Bz-HC.HCl/APAP, 4 tablets of 26.68 mg/1,300mg Bz-HC.HCl/APAP, 12 tablets of 90 mg/3,900 hydrocodonebitartrate/APAP, 8 tablets of 60 mg/2,600 mg hydrocodonebitartrate/APAP, or 4 tablets of 30 mg/1,300 mg hydrocodonebitartrate/APAP. Tablets were administered orally.

Subjects completed an initial screening visit to determine eligibilityfor the study. Eligible subjects completed a 3-day in-clinicqualification phase and a 21-day in-clinic treatment phase, with thefollow-up visit 7±2 days later. Overall study duration was approximately75 days, depending on the length of time between study visits.

Blood samples for pharmacokinetic analysis were collected prior to andup to 24 hours postdose. Plasma concentration-time data for hydrocodonefor the first 2 hours postdose are plotted in FIG. 35.

The first postdose quantifiable hydrocodone concentrations were observedat the 0.50-hour sample time for all treatments. The highest mean plasmaconcentrations were 178000±109000 pg/mL at 0.50 h for 80.04 mgBz-HC.HCl/3,900 mg APAP, 130000±70900 pg/mL at 0.50 h for 53.36 mgBz-HC.HCl/2,600 mg APAP, 63100±18300 pg/mL at 1.00 h for 26.68 mgBz-HC.HCl/1,300 mg APAP, 208000±115000 pg/mL at 0.50 h for 90 mgHB/3,900 mg APAP, 146000±69100 pg/mL at 0.50 h for 60 mg HB/2,600 mgAPAP, and 65700±22100 pg/mL at 1.00 h for 30 mg HB/1,300 mg APAP.Quantifiable concentrations of hydrocodone were observed throughout the24-hour sampling interval for all subjects.

A summary of the PK data for hydrocodone is presented in Tables 40-43.The table 40 contains descriptive statistics of the PK parameters ofhydrocodone and detailed comparisons of the log-transformed values ofAUC_(0-0.5)) AUC₀₋₁, AUC₀₋₂, AUC₀₋₄, AUC₀₋₈, AUC₀₋₂₄) AUC_(last),AUC_(inf), and C_(max). Results of analysis of variance (ANOVA) for thelog-transformed values of hydrocodone AUC_(0-0.5), AUC₀₋₁, AUC₀₋₂,AUC₀₋₄, AUC₀₋₈, AUC₀₋₂₄, AUC_(0-last), AUC_(0-inf), and C_(max)comparing corresponding doses of Bz-HC.HCl/APAP and HB/APAP aresummarized in Tables 41-43.

Hydrocodone: Bz-HC.HCl/APAP vs. HB/APAP

The administration of the high-dose (12 tablets) of Bz-HC.HCl/APAPcompared to the high-dose (12 tablets) of HB/APAP resulted in areduction of peak hydrocodone exposure (C_(max)) of approximately 11.5%(p=0.0134) and in a reduction in cumulative systemic hydrocodoneexposure as measured by AUC₀₋₁, AUC₀₋₂, AUC₀₋₄, AUC₀₋₈, and AUC₀₋₂₄ ofapproximately 15.8% (p=0.0323), 12.0% (p=0.0105), 9.1% (p=0.0102), 7.7%(p=0.0017), and 4.8% (p=0.0243), respectively. The administration of themid-dose (8 tablets) of Bz-HC.HCl/APAP compared to the mid-dose (8tablets) of HB/APAP resulted in a reduction in C_(max) of approximately10% (p=0.0333) and in a reduction in cumulative systemic hydrocodoneexposure as measured by AUC₀₋₂, AUC₀₋₄, AUC₀₋₈, and AUC₀₋₂₄ ofapproximately 9.7% (p=0.0416), 8.4% (p=0.0181), 7.5% (p=0.0022), and5.4% (p=0.0110), respectively. The administration of low-dose (4tablets) Bz-HC.HCl/APAP resulted in similar maximum, early, and totalsystemic hydrocodone exposure when compared to the low-dose (4 tablets)of HB/APAP.

TABLE 40 Descriptive Statistics of Pharmacokinetic Parameters ofHydrocodone 80.04 mg Bz-HC•HCl/ 53.36 mg Bz-HC•HCl/ 26.68 mg Bz-HC•HCl/3,900 mg APAP 2,600 mg APAP 1,300 mg APAP Parameter Mean SD Mean SD MeanSD T_(max) (h) 1.05 0.83 1.05 0.78 1.17 1.51 C_(max) (pg/mL) 20800087300 147000 54100 75100 25500 AUC_(last) (h * pg/mL) 1218000 297000812300 175300 382300 81340 AUC_(inf) (h * pg/mL) 1272000 326500 842100190800 392800 86300 AUC_(Extrap) (%) 3.81 5.12 3.29 2.50 3.14 1.67 λ_(z)(h⁻¹) 0.1471 0.0273 0.1451 0.0238 0.1423 0.0228 T_(1/2) (h) 5.00 1.794.92 0.95 4.99 0.79 T_(last) (h) 24.11 0.04 24.10 0.02 24.10 0.02C_(last) (pg/mL) 6050 4740 3780 2460 1700 945 T_(lag) (h) 0.00 0.00 0.000.00 0.00 0.00 AUC_(0-0.5) (h * pg/mL) 37140 22750 26900 14770 125307213 AUC₀₋₁ (h * pg/mL) 121900 65280 88750 42380 42520 20200 AUC₀₋₂ (h *pg/mL) 263500 103300 193400 66470 95850 29510 AUC₀₋₄ (h * pg/mL) 487500154300 353500 97670 172200 39550 AUC₀₋₈ (h * pg/mL) 816300 208800 566900128200 269000 51840 AUC₀₋₂₄ (h * pg/mL) 1217000 296800 811900 175100382100 81260 90 mg HB/ 60 mg HB/ 30 mg HB/ 3,900 mg APAP 2,600 mg APAP1,300 mg APAP Parameter Mean SD Mean SD Mean SD T_(max) (h) 1.09 1.130.99 0.65 0.95 0.37 C_(max) (pg/mL) 229000 95800 163000 52800 7790026600 AUC_(last) (h * pg/mL) 1271000 302200 862300 195100 92940 23.91AUC_(inf) (h * pg/mL) 1310000 314700 888500 205100 400200 96620AUC_(Extrap) (%) 2.92 1.97 2.82 1.88 2.79 1.27 λ_(z) (h⁻¹) 0.1533 0.02370.1504 0.0218 0.1458 0.0210 T_(1/2) (h) 4.63 0.75 4.71 0.71 4.85 0.69T_(last) (h) 24.11 0.04 24.11 0.02 24.10 0.02 C_(last) (pg/mL) 5470 31203610 2290 1560 711 T_(lag) (h) 0.00 0.00 0.00 0.00 0.00 0.00 AUC_(0-0.5)(h * pg/mL) 43140 23950 30330 14280 12930 7554 AUC₀₋₁ (h * pg/mL) 14030070120 99040 41360 43970 21690 AUC₀₋₂ (h * pg/mL) 294700 119100 21320065860 100400 35960 AUC₀₋₄ (h * pg/mL) 530200 182800 386500 103500 18190053670 AUC₀₋₈ (h * pg/mL) 874700 231300 614700 139700 281500 68710AUC₀₋₂₄ (h * pg/mL) 1270000 302000 861900 195000 388500 92890

TABLE 41 Statistical Analysis of the Natural Log-Transformed SystemicExposure Parameters of Hydrocodone Comparing 80.04 mg Bz-HC•HCl/3,900 mgAPAP to 90 mg HB/3,900 mg APAP Ratio (%)^(b) 90% CI^(c) DependentVariable (Test/Ref) Lower Upper In(C_(max)) 88.46 81.55 95.95In(AUC_(0-0.5)) 82.01 68.47 98.22 In(AUC₀₋₁) 84.21 73.80 96.09In(AUC₀₋₂) 87.97 81.03 95.49 In(AUC₀₋₄) 90.90 85.53 96.61 In(AUC₀₋₈)92.32 88.55 96.25 In(AUC₀₋₂₄) 95.17 91.79 98.67 In(AUC_(last)) 95.1791.80 98.67 In(AUC_(inf)) 96.42 93.23 99.72 ^(a)Geometric Mean for 80.04mg Bz-HC•HCl/3,900 mg APAP (Test) and 90 mg HB/3,900 mg APAP (Ref) basedon Least Squares Mean of log-transformed parameter values ^(b)Ratio (%)= Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 42 Statistical Analysis of the Natural Log-Transformed SystemicExposure Parameters of Hydrocodone Comparing 53.36 mg Bz-HC•HCl/2,600 mgAPAP to 60 mg HB/2,600 mg APAP Ratio (%)^(b) 90% CI^(c) DependentVariable (Test/Ref) Lower Upper In(C_(max)) 90.00 82.97 97.62In(AUC_(0-0.5)) 86.23 72.00 103.28 In(AUC₀₋₁) 89.02 78.02 101.57In(AUC₀₋₂) 90.32 83.21 98.05 In(AUC₀₋₄) 91.61 86.20 97.36 In(AUC₀₋₈)92.49 88.71 96.43 In(AUC₀₋₂₄) 94.56 91.20 98.03 In(AUC_(last)) 94.5691.21 98.04 In(AUC_(inf)) 95.12 91.98 98.38 ^(a)Geometric Mean for 53.36mg Bz-HC•HCl/2,600 mg APAP (Test) and 60 mg HB/2,600 mg APAP (Ref) basedon Least Squares Mean of log-transformed parameter values ^(b)Ratio (%)= Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 43 Statistical Analysis of the Natural Log-Transformed SystemicExposure Parameters of Hydrocodone Comparing 26.68 mg Bz-HC•HCl/1,300 mgto 30 mg HB/1,300 mg APAP Ratio (%)^(b) 90% CI^(c) Dependent Variable(Test/Ref) Lower Upper In(C_(max)) 96.85 89.40 104.93 In(AUC_(0-0.5))99.09 82.97 118.35 In(AUC₀₋₁) 99.04 86.98 112.78 In(AUC₀₋₂) 97.31 89.75105.50 In(AUC₀₋₄) 96.23 90.63 102.18 In(AUC₀₋₈) 96.22 92.35 100.25In(AUC₀₋₂₄) 98.08 94.66 101.63 In(AUC_(last)) 98.09 94.66 101.63In(AUC_(inf)) 97.32 94.14 100.61 ^(a)Geometric Mean for 26.68 mgBz-HC•HCl/1,300 mg APAP (Test) and 30 mg HB/1,300 mg APAP (Ref) based onLeast Squares Mean of log-transformed parameter values ^(b)Ratio (%) =Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

Results of the ANOVA for the log-transformed values of hydrocodoneAUC_(0-0.5), AUC₀₋₁, AUC₀₋₂, AUC₀₋₄, AUC₀₋₈, AUC₀₋₂₄, AUC_(0-last))AUC_(0-inf) and C_(max) comparing corresponding doses of Bz-HC.HCIL/APAPand HB/APAP are summarized in Table 41, Table 42, and Table 43.

Hydrocodone: Bz-HC.HCl/APAP vs. HB/APAP Bz-HC.HCl Example 22:Bz-HC.HCl/APAP Single Dose Intranasal Human Pharmacokinetic Studies

This was a randomized, double-blind, double-dummy, placebo-controlled,single-dose, two-part, five-way crossover study to determine therelative bioavailability, abuse potential, and safety of equivalentdoses compared with Bz-HC.HCl/APAP with HB/APAP. Subjects received 2intact oral tablets of 13.34 mg/650 mg Bz-HC.HCl/APAP, 2 crushedintranasal tablets of 13.34 mg/650 mg Bz-HC.HCl/APAP, 2 crushedintranasal tablets of 15 mg/650 HB/APAP, or 2 intact oral tablets of 15mg/650 mg HB/APAP. Tablets were administered orally or intranasally.

Subjects completed an initial screening visit to determine eligibilityfor the study. Eligible subjects completed the study for up to nineweeks for dose selection phase. Eligible subjects completed the studyfor up to fifteen weeks for main treatment study phase. Subjects whoparticipated in both dose selection and main treatment study phase mayhave participated up to twenty-four weeks.

PK blood samples for the determination of Bz-HC.HCl, hydrocodone,hydromorphone, and APAP in plasma were collected during the doseselection phase and the main study treatment phase.

Bz-HC in Plasma

The first post-dose quantifiable concentration of Bz-HCl was observed atthe 0.08-hour (5 minute) sample time. The mean peak Bz-HC concentrationwas 12500±9090 pg/mL occurring at 0.25 hours following intranasaladministration of crushed tablets of 13.34 mg/650 mg Bz-HC.HCl. Bz-HCplasma concentrations were below the limit of quantification after 8hours post-dose for most subjects.

As shown in Table 44, the mean Bz-HC C_(max) was 14800±10500 pg/mL. Themedian time to observed C_(max) was 0.45 hours. Mean AUC_(last) andAUC_(inf) were 13250±8864 h·pg/mL and 13340±8860 h·pg/mL, respectively.

Mean T_(1/2) was 1.11 hours. The median time of the last quantifiableBz-HC concentration was observed at 6.22 hours (range from 4.22 to 8.23hours).

TABLE 44 Pharmacokinetic parameters of Bz-HC in plasma following singleintranasal crushed and oral intact doses of Bz-HC•HCl/APAP for the maintreatment study phase IN crushed Bz-HC•HCl/APAP (13.34/650 mg) Parameter(N = 43) C_(max) (pg/mL) Mean (SD) 14800 (10500) T_(max) (h) Median 0.45Range 0.25-0.75 AUC_(0-0.5) (h · pg/mL) Mean (SD)  4491 (3688) AUC₀₋₁ (h· pg/mL) Mean (SD)  8577 (6249) AUC₀₋₂ (h · pg/mL) Mean (SD) 11470(8044) AUC₀₋₄ (h · pg/mL) Mean (SD) 12860 (8667) AUC₀₋₈ (h · pg/mL) Mean(SD) 13280 (8846) AUC₀₋₂₄ (h · pg/mL) Mean (SD) 13330 (8860) AUC_(last)(h · pg/mL) Mean (SD) 13250 (8864) AUC_(inf) (h · pg/mL) Mean (SD) 13340(8860) AUC_(Extrap) (h · pg/mL) Mean (SD)  0.98 (1.51) T_(1/2) (h) Mean(SD)  1.11 (0.36) C_(last) (pg/mL) Mean (SD)  53.1 (29.7) T_(last) (h)Median 6.22 Range 4.22-8.23 APAP = acetaminophen; AUC = area under thecurve; IN = intranasal; SD = standard deviation

The first post-dose quantifiable concentrations of hydrocodone wereobserved at the 0.08-hour (5-minute) sample time for all treatments. Asshown in FIG. 36, mean hydrocodone concentrations were similar acrosstreatments and mean peak concentrations were observed at approximately 1hour post-dose for all treatments. Mean peak hydrocodone concentrationsranged from 32300±7050 pg/mL (IN crushed Bz-HC.HCl/APAP) to 36000±12400pg/mL (oral intact HB/APAP). Quantifiable concentrations of hydrocodonewere observed throughout the 24-hour sampling interval for all subjects.

Descriptive statistics for the PK parameters of hydrocodone arepresented by dose level in Table 45 and inferential statistical resultsfor the treatment comparisons of interest are presented in Table 46.

As shown in Table 45, the median time to peak hydrocodone concentration(T_(max)) was observed between 1.22 and 1.23 hours across treatments.Bz-HC.HCl

Mean T_(1/2) values were similar across IN crushed and oral intactBz-HC.HCl/APAP and HB/APAP treatments; ranging from 5.14 hours (oralintact Bz-HC.HCl/APAP) to 5.23 hours (IN crushed Bz-HC.HCl/APAP).

TABLE 45 Pharmacokinetic parameters of hydrocodone in plasma followingsingle intranasal crushed and oral intact doses of Bz-HC•HCl/APAP orHB/APAP for the main treatment phase. IN crushed Bz-HC•HCl/ IN crushedAPAP HB/APAP (13.34/650 mg) (15/650 mg) Parameter (N = 43) (N = 43)C_(max) (pg/mL) Mean (SD) 34700 (8690)  39100 (11500) T_(max) (h) Median1.23 1.22 Range 0.52-2.23 0.25-2.23 AUC_(0-0.5) Mean (SD)  4767 (2313) 9341 (3836) (h · pg/mL) AUC₀₋₁ (h · pg/mL) Mean (SD) 18640 (6222) 26310(8697) AUC₀₋₂ (h · pg/mL) Mean (SD)  50120 (12060)  59130 (15250) AUC₀₋₄(h · pg/mL) Mean (SD) 103200 (23210) 111500 (25610) AUC₀₋₈ (h · pg/mL)Mean (SD) 173300 (38750) 179300 (38870) AUC₀₋₂₄ Mean (SD) 264800 (67650)264800 (60470) (h · pg/mL) AUC_(last) (h · pg/mL) Mean (SD) 265200(67820) 265100 (60590) AUC_(inf) (h · pg/mL) Mean (SD) 278300 (75130)276600 (65290) AUC_(Extrap) (%) Mean (SD)  4.33 (2.16)  3.94 (1.67)T_(1/2) (h) Mean (SD)  5.23 (0.87)  5.18 (0.69) C_(last) (pg/mL) Mean(SD) 1600 (869) 1460 (660) T_(last) (h) Median 24.22  24.22  Range24.20-24.30 24.20-24.32 APAP = acetaminophen; AUC = area under thecurve; HB = hydrocodone bitartrate; IN = intranasal; SD = standarddeviation

Statistical comparisons of the maximum (C_(max)) and cumulative (AUC)exposure parameters of hydrocodone between treatment comparisons ofinterest are presented in Table 46 and significant results are presentedbelow:

For the comparison of IN crushed Bz-HC.HCl/APAP versus IN crushedHB/APAP, early systemic hydrocodone exposures as measured byAUC_(0-0.5)) AUC₀₋₁, AUC₀₋₂, and AUC₀₋₄ were reduced by approximately50.1% (p=0.0044), 29.1% (p=0.0005), 14.9% (p=0.0003), and 7.3%(p=0.0053), respectively.

For the comparison of IN crushed Bz-HC.HCl/APAP versus IN crushedHB/APAP, peak hydrocodone plasma concentration (C_(max)) was reduced byapproximately 10.6% (p=0.0027).

TABLE 46 Inferential Statistical Results of the PharmacokineticParameters of Hydrocodone for the Treatment Phase (PK Population). Ratio(%)^(b) 90% CI^(c) Dependent Variable (Test/Ref) Lower Upper In(C_(max))89.35 84.07 94.97 In(AUC_(0-0.5)) 49.93 33.60 74.22 In(AUC₀₋₁) 70.9360.56 83.08 In(AUC₀₋₂) 85.12 79.17 91.52 In(AUC₀₋₄) 92.67 88.65 96.88In(AUC₀₋₈) 96.60 93.11 100.22 In(AUC₀₋₂₄) 99.58 95.86 103.44In(AUC_(last)) 99.58 95.83 103.48 In(AUC_(inf)) 100.01 96.17 104.01^(a)Geometric Mean for crushed intranasal 13.34 mg Bz-HC•HCl/650 mg APAP(Test) and crushed intranasal 15 mg HB/650 mg APAP (Ref) based on LeastSquares Mean of log-transformed parameter values ^(b)Ratio (%) =Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

Pharmacokinetic Conclusions

For Bz-HC.HCl:

Quantifiable concentrations of Bz-HC.HCl were observed only for the INcrushed Bz-HC.HCl/APAP (13.34/650 mg) treatment. Concentrations ofBz-HC.HCl were not detected after administration of oral intactBz-HC.HCl/APAP (13.34/650 mg).

Mean T_(1/2) of Bz-HC.HCl was 1.11 hours.

The median time of the last quantifiable Bz-HC.HCl concentration wasobserved at 6.22 hours (range from 4.22 to 8.23 hours) following asingle dose of IN crushed Bz-HC.HCl/APAP (13.34/650 mg).

For Hydrocodone

Statistically significant reduction in peak hydrocodone exposure(C_(max)) and early cumulative hydrocodone exposure (AUC_(0-0.5)) AUC₀₋₁AUC₀₋₂, and AUC₀₋₄) was observed for the comparison of IN crushedBz-HC.HCl/APAP and IN crushed HB/APAP.

A statistically significant difference in T_(max) values of hydrocodonewas observed between IN crushed Bz-HC.HCl/APAP and IN crushed HB/APAP(median [range] of 1.23 [0.52-2.23] versus 1.22 [0.25-2.23] hours,respectively).

No statistically significant differences in T_(1/2) and λz values forhydrocodone were observed for any of the comparisons evaluated.

Example 23: Bz-HC.HCl Single Dose Intranasal Human PharmacokineticStudies

This was a randomized, double blind, single dose, two way crossover,single center study in recreational non-dependent opioid users. Subjectsparticipated in a Screening Phase (Visit 1), Naloxone Challenge Test(Visit 2, Check in), Treatment Phase (Visit 2, inpatient) and Follow upPhase (Visit 3).

A sufficient number of male and female subjects between the ages of18-55 years were to be screened in order to enroll approximately 30subjects into the Treatment Phase to ensure 24 completers.

Mean plasma hydrocodone concentrations over time are illustrated inin-text FIG. 36. The first post dose quantifiable hydrocodoneconcentrations were observed at the 0.083 hour (5 minute) post dosesample time for both treatments. Mean (SD) plasma hydrocodoneconcentrations rose rapidly following intranasal administration of HBAPI, with a peak concentration of 36700 (11400 pg/mL) at 0.5 hourpostdose. Mean (SD) peak plasma hydrocodone concentrations withBz-HC.HCl API were notably delayed (2 hours postdose) and markedly lower(21900 [4730] pg/mL) than observed with HB API. After reaching peakplasma levels, hydrocodone concentrations declined in a log linearmanner for both treatments. Quantifiable concentrations of hydrocodonewere observed throughout the 24 hour sampling interval for all subjects.Review of individual concentration time profiles supported the meanconcentration time profile, with the majority of subjects exhibiting alower and delayed peak plasma hydrocodone concentration followingintranasal administration of Bz-HC.HCl API relative to HB API.

Selected PK parameters for hydrocodone are presented below in Table 48.Cumulative partial AUCs for hydrocodone are illustrated in FIG. 37.

Bz-HC.HCl API was associated with a notably lower and delayed mean andmedian C_(max) compared to HB API, with median T_(max) delayed more than3 fold (0.5 hour [HB API] vs. 1.75 hours [Bz-HC.HCl API]). Furthermore,mean and median partial AUCs were lower for Bz-HC.HCl API relative to HBAPI at all-time points. Consistent with the partial AUCs, overallexposure (AUC_(last) and AUC_(inf)) was lower for Bz-HC.HCl API, andthis was mainly a result of the large differences seen in exposure tohydrocodone during the first 8 hours post dose.

Mean (SD) t_(1/2) were similar for Bz-HC.HCl API (5.29 [0.78] hours) andHB API (5.13 [0.74] hours).

TABLE 48 Descriptive Statistics for Selected Plasma Hydrocodone PKParameters by Treatment (PK Population) Parameter (N = 24) StatisticBz-HC•HCl API HB API C_(max) (pg/mL) Mean (SD) 25600 (6390) 40400(11800) Median (Min-Max) 25200 (17300-42400) 37800 (20300-71300) CV %24.99 29.21 T_(max) (h) Median (Min-Max) 1.75 (0.75-4.0) 0.5 (0.25-2.02)AUC_(0-0.083 h) Mean (SD) 11.30 (14.14) 391.3 (281.5) (h * pg/mL) Median(Min-Max) 4.415 (0.0-46.23) 308.2 (53.31-1229) CV % 125.08 71.94AUC_(0-0.25 h) Mean (SD) 297.9 (170.3) 3800 (1962) (h * pg/mL) Median(Min-Max) 295.5 (63.79-613.1) 3649 (632.6-9630) CV % 57.15 51.62AUC_(0-0.5 h) Mean (SD) 1485 (667.7) 12310 (5132) (h * pg/mL) Median(Min-Max) 1485 (335.7-3105) 10720 (2754-25960) CV % 44.95 41.68AUC_(0-0.75 h) Mean (SD) 3831 (1726) 21370 (7312) (h * pg/mL) Median(Min-Max) 3469 (940.3-8968) 18890 (6654-40760) CV % 45.04 34.21AUC_(0-1 h) Mean (SD) 7714 (3597) 29870 (8917) (h * pg/mL) Median(Min-Max) 7084 (2165-16090) 27660 (10800-54020) CV % 46.62 29.85AUC_(0-1.5 h) Mean (SD) 17790 45210 (h * pg/mL) Median (Min-Max) 16940(8058-34040) 43530 (18530-76790) CV % 43.25 25.75 AUC_(0-2 h) Mean (SD)28690 (10360) 59200 (13910) (h * pg/mL) Median (Min-Max) 27710(16390-51960) 57460 (27980-97220) CV % 36.11 23.49 AUC_(0-3 h) Mean (SD)49510 84140 (h * pg/mL) Median (Min-Max) 47310 (33590-80810) 82660(47940-132000) CV % 26.84 20.98 AUC_(0-4 h) Mean (SD) 68360 (15540)106000 (21000) (h * pg/mL) Median (Min-Max) 64000 (48330-104600) 101900(66490-162200) CV % 22.73 19.81 AUC_(0-6 h) Mean (SD) 99100 (20450)141200 (27530) (h * pg/mL) Median (Min-Max) 93370 (66600-143900) 137300(95690-210400) CV % 20.64 19.50 AUC_(0-8 h) Mean (SD) 121100 (25710)165600 (33550) (h * pg/mL) Median (Min-Max) 114900 (78200-182700) 159000(115500-246100) CV % 21.22 20.26 AUC_(0-10 h) Mean (SD) 137200 (30610)182500 (38250) (h * pg/mL) Median (Min-Max) 131200 (86290-213900) 178000(129100-271900) CV % 22.30 20.96 AUC_(0-12 h) Mean (SD) 149000 (34890)194500 (41790) (h * pg/mL) Median (Min-Max) 141800 (91880-238600) 194400(139200-290800) CV % 23.41 21.49 AUC_(0-24 h) Mean (SD) 185500 (50470)231000 (54620) (h * pg/mL) Median (Min-Max) 177000 (110100-317200)234700 (165600-355500) CV % 27.20 23.65 AUC_(last) Mean (SD) 185500(50470) 231000 (54640) (h * pg/mL) Median (Min-Max) 177000(110100-317200) 234700 (165600-355700) CV % 27.20 23.65 AUC_(inf) Mean(SD) 194700 (55690) 239400 (58380) (h * pg/mL) Median (Min-Max) 185500(115200-336400) 240400 (168300-371700) CV % 28.61 24.39 API = activepharmaceutical ingredient; AUC_(0-inf): area under the plasmaconcentration vs. time curve extrapolated to infinity; AUC_(last) = areaunder the plasma concentration vs. time curve from 0 to last measurableconcentration; AUC_(0-x) = area under the plasma concentration vs. timecurve from T = 0 to T = x; C_(max) = maximum observed plasmaconcentration; CV = coefficient of variation; HB = hydrocodonebitartrate; SD = standard deviation; T_(max) = time to achieve themaximum observed plasma concentration.

Inferential analysis results of PK parameters derived for hydrocodoneare provided in Table 50, Table 51 and Table 52 and selected results aresummarized Table 49 and Table 50.

C_(max) of hydrocodone and all derived total and partial AUCs weresubstantially lower for Bz-HC.HCl API compared to HB API. C_(max) forBz-HC.HCl API was approximately 36% (p<0.0001) lower and significantlydelayed compared with HB API (T_(max): Wilcoxon signed rank test,p<0.0001).

In addition to these significant differences in peak and time to peakexposure, the intranasal administration of Bz-HC.HCl API resulted in anapproximately 53% (AUC_(0-2h), p<0.0001) to 95% (AUC_(0083h), p<0.0001)reduction in early systemic hydrocodone exposure compared to HB API,depending on the time interval (with consistently greater reduction inexposure at earlier time points). Exposure to hydrocodone remained loweroverall for Bz-HC.HCl API at all-time points compared to HB API as shownby later partial and total AUCs (all p<0.0001).

TABLE 49 Inferential analysis results of selected naturallog-transformed systemic exposure parameters of hydrocodone (PKPopulation) Ratio (%)^(b) 90% CI Dependent Variable (Test/Reference)Lower Upper ln(C_(max)) 63.96 59.55 68.71 ln(AUC_(0-0.083 h)) 4.90 3.446.98 ln(AUC_(0-0.25 h)) 7.39 6.01 9.09 ln(AUC_(0-0.5 h)) 11.81 10.3413.50 ln(AUC_(0-0.75 h)) 17.24 15.42 19.27 ln(AUC_(0-1 h)) 24.22 21.2427.61 ln(AUC_(0-1.5 h)) 37.14 32.70 42.19 ln(AUC_(0-2 h)) 46.84 42.1652.05 ln(AUC_(0-3 h)) 58.16 53.94 62.71 ln(AUC_(0-4 h)) 64.15 60.4568.07 ln(AUC_(0-6 h)) 70.06 66.90 73.38 ln(AUC_(0-8 h)) 73.01 69.9576.20 ln(AUC_(0-10 h)) 74.97 71.86 78.22 ln(AUC_(0-12 h)) 76.31 73.1579.61 ln(AUC_(0-24 h)) 79.69 76.47 83.04 ln(AUC_(last)) 79.69 76.4783.04 ln(AUC_(inf)) 80.54 77.33 83.88 ^(a)Geometric Mean for intranasal13.34 mg Bz-HC•HCl API (Test) and intranasal 15 mg HB API (Ref) based onLeast Squares Mean of log-transformed parameter values ^(b)Ratio (%) =Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 50 Inferential Analysis Results of T_(max) Values for Hydrocodone(PK Population) Dependent Median^(a) Range^(a) Variable Test ReferenceTest Reference P-value T_(max) (hour) 1.75 0.50 0.75-4.00 0.25-2.02<0.0001 T_(max) = time to achieve the maximum observed plasmaconcentration. ^(a)Median and range for Bz-HC•HCl API (Test) and HB API(Reference)

Bz-HC.HCl

The first post-dose quantifiable Bz-HC concentration was observed at0.083 hour (5 minutes) post-dose for Bz-HC.HCl API. The highest mean(SD) plasma concentration was 2010 (1450) pg/mL at 0.25 hour post-dose.Bz-HC concentrations were below the limit of quantification (BLQ) forall subjects at 24 hours post-dose.

Descriptive statistics of the derived parameters for Bz-HC are presentedin Table 49 and selected parameters are presented below in in-text Table51.

TABLE 51 Descriptive Statistics for Selected Plasma PK Parameters forBz-HC (PK Population) Parameter (N = 24) Statistic Bz-HC•HCl API C_(max)(pg/mL) Mean (SD) 2410 (1900) Median (Min-Max) 2160 (160-8280) CV %79.06 T_(max) (h) Median (Min-Max) 0.25 (0.25-1.02) AUC_(0-0.0833 h)(h * pg/mL) Mean (SD) 15.34 Median (Min-Max) 5.708 (0.000-64.14) CV %121.09 AUC_(0-0.25 h) (h * pg/mL) Mean (SD) 213.3 Median (Min-Max) 196.6(17.31-496.1) CV % 73.69 AUC_(0-0.5 h) (h * pg/mL) Mean (SD) 699.9(532.1) Median (Min-Max) 666.4 (45.84-1969) CV % 76.02 AUC_(0-0.75 h)(h * pg/mL) Mean (SD) 1145 Median (Min-Max) 977.1 (61.76-4008) CV %85.57 AUC_(0-1 h) (h * pg/mL) Mean (SD) 1497 (1318) Median (Min-Max)1238 (85.29-5561) CV % 88.06 AUC_(0-1.5 h) (h * pg/mL)* Mean (SD) 2058Median (Min-Max) 1680 (373.8-7256) CV % 83.10 AUC_(0-2 h) (h * pg/mL)*Mean (SD) 2393 (2016) Median (Min-Max) 1933 (399.8-8466) CV % 84.22AUC_(0-3 h) (h * pg/mL)* Mean (SD) 2794 Median (Min-Max) 2190(449.4-10400) CV % 84.75 AUC_(0-4 h) (h * pg/mL)** Mean (SD) 3139 (2576)Median (Min-Max) 2361 (827.5-11550) CV % 82.08 AUC_(0-6 h) (h * pg/mL)**Mean (SD) 3395 (2781) Median (Min-Max) 2557 (846.2-12550) CV % 81.92AUC_(0-8 h) (h * pg/mL)** Mean (SD) 3511 (2882) Median (Min-Max) 2615(849.2-13020) CV % 82.08 AUC_(0-10 h) (h * pg/mL)** Mean (SD) 3563Median (Min-Max) 2636 (849.7-13250) CV % 82.21 AUC_(0-12 h) (h *pg/mL)** Mean (SD) 3588 Median (Min-Max) 2643 (849.8-13290) CV % 82.06AUC_(0-24 h) (h * pg/mL)** Mean (SD) 3614 Median (Min-Max) 2647(849.7-13320) CV % 81.83 AUC_(last) (h * pg/mL) Mean (SD) 3244 (2974)Median (Min-Max) 2406 (85.29-13250) CV % 91.65 AUC_(inf) (h * pg/mL)**Mean (SD) 3616 (2957) Median (Min-Max) 2646 (849.7-13320) CV % 81.79t_(1/2) (h)** Mean (SD) 1.42 (0.59) Median (Min-Max) 1.30 (0.72-2.84) CV% 41.66 API = active pharmaceutical ingredient; AUC_(0-inf): area underthe plasma concentration vs. time curve extrapolated to infinity;AUC_(last) = area under the plasma concentration vs. time curve from 0to last measurable concentration; AUC_(0-x) = area under the plasmaconcentration vs. time curve from T = 0 to T = x; C_(max) = maximumobserved plasma concentration; CV = coefficient of variation; SD =standard deviation; T_(max) = time to achieve the maximum observedplasma concentration. *= n = 23 **n = 22

There were no statistically significant differences observed inuntransformed t_(1/2) values between Bz-HC.HCl API and HB API forhydrocodone.

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

The compositions, prodrugs, and methods described herein can beillustrated by the following embodiments enumerated in the numberedclaims that follow:

1. A composition comprising at least one conjugate of hydrocodone and atleast one benzoic acid or benzoic acid derivative, a salt thereof, or acombination thereof, at least one benzoic acid or benzoic acidderivative having the following formula I:

wherein,

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

2. A composition comprising at least one conjugate of hydrocodone and atleast one benzoic acid, a derivative thereof, or a combination thereof.3. A composition comprising a benzoate conjugate, wherein the benzoateconjugate comprises at least one hydrocodone conjugated to at least onebenzoic acid or benzoic acid derivative.4. The composition of paragraph 1, wherein at least one benzoic acid orbenzoic acid derivative is an aminobenzoate, a hydroxybenzoate, anaminohydroxybenzoate, a derivative thereof, or combination thereof.5. The composition of paragraph 4, wherein the aminobenzoate is selectedfrom the group consisting of: anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid, derivatives thereof and combinationsthereof.6. The composition of paragraph 4, wherein the hydroxybenzoate isselected from the group consisting of salicylic acid, acetylsalicylicacid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid, derivatives thereof and combinationsthereof.7. The composition of paragraph 4, wherein the aminohydroxybenzoate isselected from the group consisting of 4-aminosalicylic acid,3-hydroxyanthranilic acid, 3-methoxyanthranilic acid, derivativesthereof and combinations thereof.8. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is a treatment or preventative composition used to treatnarcotic or opioid abuse or prevent withdrawal.9. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is a pain treatment composition.10. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is moderate to severe pain treatment composition.11. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate reduces or prevents oral, intranasal or intravenous drugabuse.12. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate provides oral, intranasal or parenteral drug abuse resistance.13. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to unconjugated hydrocodone over the same time period.14. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto unconjugated hydrocodone.15. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate has reduced side effects when compared with unconjugatedhydrocodone.16. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate prevents drug tampering by either physical or chemicalmanipulation.17. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is provided in a dosage form selected from the groupconsisting of: a tablet, a capsule, a caplet, a suppository, a troche, alozenge, an oral powder, a solution, an oral film, a thin strip, aslurry, and a suspension.18. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to unconjugatedhydrocodone.19. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) compared to an equivalentmolar amount of unconjugated hydrocodone.20. The composition of paragraphs 1, 2, 3, or 4, wherein at least oneconjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and a lower C_(max) compared to anequivalent molar amount of unconjugated hydrocodone.21. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.22. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.23. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.24. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.25. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.26. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.27. The composition of paragraphs 1, 2, 3 or 4, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.28. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or benzoic acid derivative, asalt thereof, or a combination thereof, the benzoic acid or benzoic acidderivative having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

29. The method of paragraph 28, wherein at least one conjugate exhibitsa slower rate of release over time and greater AUC when compared to anequivalent molar amount of unconjugated hydrocodone over the same timeperiod.30. The method of paragraph 28, wherein at least one conjugate exhibitsless variability in the oral PK profile when compared to unconjugatedhydrocodone.31. The method of paragraph 28, wherein at least one conjugate hasreduced side effects when compared with unconjugated hydrocodone.32. The method of paragraph 28, wherein at least one conjugate isprovided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.33. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC when compared to a molar equivalent amount ofunconjugated hydrocodone.34. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC and when compared to a molar equivalent amount ofunconjugated hydrocodone.35. The method of paragraph 28, wherein at least one conjugate isprovided in an amount sufficient to provide a therapeuticallybioequivalent AUC and a lower C_(max) when compared to a molarequivalent amount of unconjugated hydrocodone.36. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 0.5 mg or higher.37. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 2.5 mg or higher.38. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 5 mg or higher.39. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 10 mg or higher.40. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 20 mg or higher.41. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 50 mg or higher.42. The method of paragraph 28, wherein at least one conjugate ispresent in an amount of from about 100 mg or higher.43. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or benzoic acid derivative, asalt thereof, or a combination thereof, the benzoic acid or benzoic acidderivative having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

44. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.45. The method of paragraph 44, wherein at least one conjugate providesa slower rate of release over time and higher AUC when compared to anequivalent molar amount of unconjugated hydrocodone over the same timeperiod.46. The method of paragraph 44, wherein at least one conjugate exhibitsless variability in the oral PK profile when compared to hydrocodonealone.47. The method of paragraph 44, wherein at least one conjugate hasreduced side effects when compared with hydrocodone alone.48. The method of paragraph 44, wherein at least one conjugate isprovided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.49. The method of paragraph 44, wherein at least one conjugate isprovided in an amount sufficient to provide a bioequivalent, and thustherapeutically equivalent, AUC when compared to hydrocodone alone.50. The method of paragraph 44, wherein at least one conjugate isprovided in an amount sufficient to provide a bioequivalent, and thustherapeutically equivalent, AUC and C_(max) when compared to hydrocodonealone.51. The method of paragraph 44, wherein at least one conjugate isprovided in an amount sufficient to provide a bioequivalent, and thustherapeutically equivalent, AUC when compared to hydrocodone alone witha lower C_(max).52. The method of paragraph 44, wherein at least one conjugate isprovided in an amount sufficient to provide a bioequivalent, and thustherapeutically equivalent, AUC when compared to hydrocodone alone, butdoes not provide an equivalent C_(max).53. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 0.5 mg or higher.54. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 2.5 mg or higher.55. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 5 mg or higher.56. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 10 mg or higher.57. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 20 mg or higher.58. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 50 mg or higher.59. The method of paragraph 44, wherein at least one conjugate ispresent in an amount of from about 100 mg or higher.60. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.61. The method of paragraph 60, wherein at least one conjugatereversibly inhibits binding of an opioid to the opioid receptor of thepatient.62. A pharmaceutical kit comprising:

-   -   a specified amount of individual doses in a package containing a        pharmaceutically effective amount of at least one conjugate of        hydrocodone and at least one benzoic acid or benzoic acid        derivative, a salt thereof, or a combination thereof, the        benzoic acid or benzoic acid derivative having the formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q can be independently selected from 0 or 1; and

x is an integer between 1 and 10

63. The kit of paragraph 62, wherein the kit further comprises:

-   -   instructions for use of the kit in a method for treating or        preventing drug withdrawal symptoms or pain in a human or animal        patient.        64. The kit of paragraph 63, wherein the patient is a pediatric        patient.        65. The kit of paragraph 63, wherein the patient is an elderly        patient.        66. The kit of paragraph 63, wherein the patient is a normative        patient.        67. A pharmaceutical kit comprising:    -   a specified amount of individual doses in a package containing a        pharmaceutically effective amount of at least one conjugate of        hydrocodone and at least one benzoic acid, a salt thereof, a        derivative thereof or a combination thereof.        68. The kit of paragraph 67, wherein the kit further comprises:    -   instructions for use of the kit in a method for treating or        preventing drug withdrawal symptoms or pain in a human or animal        patient.        69. The kit of paragraph 68, wherein the patient is a pediatric        patient.        70. The kit of paragraph 68, wherein the patient is an elderly        patient.        71. The kit of paragraph 68, wherein the patient is a normative        patient.        72. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 0.5 mg or higher of        at least one conjugate.        73. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 2.5 mg or higher of        at least one conjugate.        74. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 5.0 mg or higher of        at least one conjugate.        75. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 10 mg or higher of at        least one conjugate.        76. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 20 mg or higher of at        least one conjugate.        77. The kit of paragraph 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 50 mg or higher of at        least one conjugate.        78. The kit of paragraphs 62, 63, 67, or 68, wherein the        individual dosages comprise at least about 100 mg or higher of        at least one conjugate.        79. The kit of paragraphs 62, 63, 67, or 68, wherein the kit        comprises from about 1 to about 60 individual doses.        80. The kit of paragraphs 62, 63, 67, or 68, wherein the kit        comprises from about 10 to about 30 individual doses.        81. A composition comprising at least one conjugate of        hydrocodone and at least one heteroaryl carboxylic acid, a        derivative thereof, or a combination thereof.        82. The composition of paragraph 81, wherein at least one        heteroaryl carboxylic acid is selected from formula II, formula        III or formula IV, wherein formula II, formula III and formula        IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

83. A composition comprising at least one conjugate of hydrocodone andat least one nicotinic acid, a derivative thereof, or a combinationthereof.84. The composition of paragraph 81, wherein at least one heteroarylcarboxylic acid is a pyridine derivative.85. The composition of paragraph 81, wherein the heteroaryl carboxylicacid is selected from the group consisting of, isonicotinic acid,picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid,citrazinic acid, 2,6-dihydroxynicotinic acid, kynurenic acid,xanthurenic acid, 6-hydroxykynurenic acid, 8-methoxykynurenic acid,7,8-dihydroxykynurenic acid, 7,8-dihydro-7,8-dihydroxykynurenic acid,derivatives thereof and combinations thereof.86. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is used to treat drug, narcotic or opioid abuse or preventwithdrawal.87. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is used to treat pain.88. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is used to treat moderate to severe pain.89. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate reduces or prevents oral, intranasal or intravenous drugabuse.90. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate provides oral, intranasal or parenteral drug abuse resistance.91. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate prevents drug tampering by either physical or chemicalmanipulation.92. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to a molar equivalent of unconjugated hydrocodone alone overthe same time period.93. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto a molar equivalent of unconjugated hydrocodone alone.94. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate has reduced side effects when compared with hydrocodone alone.95. The composition of paragraphs 81, 82, or 83, wherein the compositionis provided in a dosage form selected from the group consisting of: atablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oralpowder, a solution, an oral film, a thin strip, a slurry, and asuspension.96. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC when compared toa molar equivalent of unconjugated hydrocodone alone.97. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC and C_(max) whencompared to hydrocodone alone.98. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC when compared tohydrocodone alone, with a lower C_(max).99. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.100. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.101. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.102. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.103. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.104. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.105. The composition of paragraphs 81, 82, or 83, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.106. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid.107. The method of paragraph 106, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

108. A method for treating a patient having a disease, disorder orcondition requiring or mediated by binding of an opioid to one or moreopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.109. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate exhibits an improved rate of release over time and AUC whencompared to hydrocodone alone over the same time period.110. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate exhibits less variability in the oral PK profile when comparedto hydrocodone alone.111. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate has reduced side effects when compared to hydrocodone alone.112. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is provided in a dosage from selected from the groupconsisting of: a tablet, a capsule, a caplet, a suppository, a troche, alozenge, an oral powder, a solution, an oral film, a thin strip, aslurry, and a suspension.113. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC when compared toan equivalent molar amount of unconjugated hydrocodone.114. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC and C_(max) whencompared to an equivalent molar amount of unconjugated hydrocodone.115. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC and a lowerC_(max) compared to the same molar amount of unconjugated hydrocodone.116. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is provided in an amount sufficient to provide abioequivalent, and thus therapeutically equivalent, AUC when compared tohydrocodone alone, but does not provide an equivalent C_(max).117. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 0.5 mg or higher.118. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 2.5 mg or higher.119. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 5 mg or higher.120. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 10 mg or higher.121. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 20 mg or higher.122. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 50 mg or higher.123. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate is present in an amount of from about 100 mg or higher.124. The method of paragraphs 106, 107, or 108, wherein at least oneconjugate binds reversibly to one or more opioid receptors of thepatient.125. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid.126. The method of paragraph 125, wherein at least one heteroarylcarboxylic acid is selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

127. A method for treating a patient having a disease, disorder orcondition requiring or mediated by inhibiting binding of an opioid toopioid receptors of the patient, comprising orally administering to thepatient a pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.128. A pharmaceutical kit comprising:

-   -   a specified number of individual doses in a package containing a        pharmaceutically effective amount of at least one conjugate of        hydrocodone and at least one heteroaryl carboxylic acid, a        derivative thereof, or a combination thereof, wherein at least        one heteroaryl carboxylic acid is selected from formula II,        formula III or formula IV, wherein formula II, formula III and        formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

129. The kit of paragraph 128, wherein the kit further comprises:instructions for use of the kit in a method for treating or preventingdrug withdrawal symptoms or pain in a human or animal patient.130. The kit of paragraph 129, wherein the patient is a pediatricpatient.131. The kit of paragraph 129, wherein the patient is an elderlypatient.132. The kit of paragraph 129, wherein the patient is a normativepatient.133. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 0.5 mg or higher of at least one conjugate.134. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 2.5 mg or higher of at least one conjugate.135. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 5.0 mg or higher of at least one conjugate.136. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 10 mg or higher of at least one conjugate.137. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 20 mg or higher of at least one conjugate.138. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 50 mg or higher of at least one conjugate.139. The kit of paragraphs 128 or 129, wherein the individual dosagescomprise at least about 100 mg or higher of at least one conjugate.140. The kit of paragraphs 128 or 129, wherein the kit comprises fromabout 1 to about 60 individual doses.141. The kit of paragraphs 128 or 129, wherein the kit comprises fromabout 10 to about 30 individual doses.142. A prodrug comprising at least one conjugate of hydrocodone and atleast one benzoic acid or benzoic acid derivative, a salt thereof, a ora combination thereof, the benzoic acid or benzoic acid derivativehaving the following formula I:

wherein,

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer between 1 and 10.

143. A prodrug comprising at least one conjugate of hydrocodone and atleast one benzoic acid, a derivative thereof, or a combination thereof.144. A prodrug comprising a benzoate conjugate, wherein the benzoateconjugate comprises at least one hydrocodone conjugated to at least onebenzoic acid or benzoic acid derivative.145. A prodrug comprising at least one conjugate of hydrocodone and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof.146. The prodrug of paragraph 145, wherein the heteroaryl carboxylicacid is selected from formula II, formula III or formula IV, whereinformula II, formula III and formula IV are:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—;

R¹, R² and R³ are independently selected from the group consisting of H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl;

o, p, q are independently selected from 0 or 1; and

x is an integer from 1 to 10.

147. A prodrug comprising at least one conjugate of hydrocodone and atleast one nicotinic acid, a derivative thereof, or a combinationthereof.148. The prodrug of paragraph 142, wherein the benzoic acid derivativeis an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, aderivative thereof, or combination thereof.149. The composition of paragraphs 1 or 2, wherein at least oneconjugate exhibits less variability in intranasal PK profiles whencompared to unconjugated hydrocodone.150. The composition of paragraphs 1 or 2, wherein at least oneconjugate exhibits less variability in the parenteral PK profiles whencompared to unconjugated hydrocodone.151. The composition of paragraphs 1 or 2, wherein at least oneconjugate exhibits less variability in the intravenous PK profile whencompared to unconjugated hydrocodone.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the technology and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

1-75. (canceled)
 76. A compound having the following chemical structure:

or a salt thereof.
 77. The compound of claim 76, wherein the salt is apharmaceutically acceptable salt.
 78. The compound of claim 77, whereinthe salt is selected from the group consisting of acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.
 79. A compound having the following chemical structure:

or a salt thereof.
 80. The compound of claim 79, wherein the salt is apharmaceutically acceptable salt.
 81. The compound of claim 80, whereinthe salt is selected from the group consisting of acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.
 82. A compound having the following chemical structure:

or a salt thereof.
 83. The compound of claim 82, wherein the salt is apharmaceutically acceptable salt.
 84. The compound of claim 83, whereinthe salt is selected from the group consisting of acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.
 85. A compound having the following chemical structure:

or a salt thereof.
 86. The compound of claim 85 wherein the salt is apharmaceutically acceptable salt.
 87. The compound of claim 86, whereinthe salt is selected from the group consisting of acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.
 88. A compound having the following chemical structure:

or a salt thereof.
 89. The compound of claim 88, wherein the salt is apharmaceutically acceptable salt.
 90. The compound of claim 89, whereinthe salt is selected from the group consisting of acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.
 91. A pharmaceutical kit comprising: a specified amount ofindividual doses, wherein each individual dose comprises apharmaceutically effective amount of at least one compound, or apharmaceutically acceptable salt thereof, having the following chemicalstructure:

and instructions for use.
 92. The pharmaceutical kit of claim 91,wherein the instructions for use comprise a method for treating orpreventing drug withdrawal symptoms in a human or animal patient. 93.The pharmaceutical kit of claim 91, wherein the instructions for usecomprise a method for treating pain in a human or animal patient. 94.The pharmaceutical kit of claim 91, wherein the individual dose furthercomprises at least one carrier.
 95. The pharmaceutical kit of claim 94,wherein the at least one carrier is at least one biologically acceptablecarrier.
 96. The pharmaceutical kit of claim 95, wherein the individualdose comprises at least about 0.5 mg to about 100 mg of the at least onecompound.
 97. The pharmaceutical kit of claim 95, wherein the individualdose comprises at least about 5 mg to about 10 mg of the at least onecompound.
 98. The pharmaceutical kit of claim 95, wherein the kitcomprises from about 1 to about 60 individual doses.
 99. Thepharmaceutical kit of claim 95, wherein the kit comprises from about 10to about 30 individual doses.
 100. The pharmaceutical kit of claim 95,wherein the kit comprises from about 12 to about 28 individual doses.101. A pharmaceutical kit comprising: a specified amount of individualdoses, wherein each individual dose comprises a pharmaceuticallyeffective amount of at least one compound, or a pharmaceuticallyacceptable salt thereof, having the following chemical structure:

and instructions for use.
 102. The kit of claim 101, wherein theinstructions for use comprise a method for treating or preventing drugwithdrawal symptoms in a human or animal patient.
 103. The kit of claim101, wherein the instructions for use comprise a method for treatingpain in a human or animal patient.
 104. The kit of claim 101, whereinthe individual dose further comprises at least one carrier.
 105. The kitof claim 104, wherein the at least one carrier is at least onebiologically acceptable carrier.
 106. The kit of claim 105, wherein theindividual dose comprises at least about 0.5 mg to about 100 mg of theat least one compound.
 107. The kit of claim 105, wherein the individualdose comprises at least about 5 mg to about 10 mg of the at least onecompound.
 108. The kit of claim 105, wherein the kit further comprisesfrom about 1 to about 60 individual doses.
 109. The kit of claim 105,wherein the kit comprises from about 10 to about 30 individual doses.110. The kit of claim 105, wherein the kit further comprises from about12 to about 28 individual doses.
 111. A pharmaceutical kit comprising: aspecified amount of individual doses, wherein each individual dosecomprises a pharmaceutically effective amount of at least one compound,or a pharmaceutically acceptable salt thereof, having the followingchemical structure:

and instructions for use.
 112. The pharmaceutical kit of claim 111,wherein the instructions for use comprise a method for treating orpreventing drug withdrawal symptoms in a human or animal patient. 113.The pharmaceutical kit of claim 111, wherein the instructions for usecomprise a method for treating pain in a human or animal patient. 114.The pharmaceutical kit of claim 111, wherein the individual dose furthercomprises at least one carrier.
 115. The pharmaceutical kit of claim114, wherein the at least one carrier is at least one biologicallyacceptable carrier.
 116. The pharmaceutical kit of claim 115, whereinthe individual dose comprises at least about 0.5 mg to about 100 mg ofthe at least one compound.
 117. The pharmaceutical kit of claim 115,wherein the individual dose comprises at least about 5 mg to about 10 mgof the at least one compound.
 118. The pharmaceutical kit of claim 115,wherein the kit further comprises from about 1 to about 60 individualdoses.
 119. The pharmaceutical kit of claim 115, wherein the kitcomprises from about 10 to about 30 individual doses.
 120. Thepharmaceutical kit of claim 115, wherein the kit further comprises fromabout 12 to about 28 individual doses.
 121. A pharmaceutical kitcomprising: a specified amount of individual doses, wherein eachindividual dose comprises a pharmaceutically effective amount of atleast one compound, or a pharmaceutically acceptable salt thereof,having the following chemical structure:

and instructions for use.
 122. The pharmaceutical kit of claim 121,wherein the instructions for use comprise a method for treating orpreventing drug withdrawal symptoms in a human or animal patient. 123.The pharmaceutical kit of claim 121, wherein the instructions for usecomprise a method for treating pain in a human or animal patient. 124.The pharmaceutical kit of claim 121, wherein the individual dose furthercomprises at least one carrier.
 125. The pharmaceutical kit of claim124, wherein the at least one carrier is at least one biologicallyacceptable carrier.
 126. The pharmaceutical kit of claim 125, whereinthe individual dose comprises at least about 0.5 mg to about 100 mg ofthe at least one compound.
 127. The pharmaceutical kit of claim 125,wherein the individual dose comprises at least about 5 mg to about 10 mgof the at least one compound.
 128. The pharmaceutical kit of claim 125,wherein the kit further comprises from about 1 to about 60 individualdoses.
 129. The pharmaceutical kit of claim 125, wherein the kitcomprises from about 10 to about 30 individual doses.
 130. Thepharmaceutical kit of claim 125, wherein the kit further comprises fromabout 12 to about 28 individual doses.
 131. A pharmaceutical kitcomprising: a specified amount of individual doses, wherein eachindividual does comprises a pharmaceutically effective amount of atleast one compound, or a pharmaceutically acceptable salt thereof,having the following chemical structure:

and instructions for use.
 132. The pharmaceutical kit of claim 131,wherein the instructions for use comprise a method for treating orpreventing drug withdrawal symptoms in a human or animal patient. 133.The pharmaceutical kit of claim 131, wherein the instructions for usecomprise a method for treating pain in a human or animal patient. 134.The pharmaceutical kit of claim 131, wherein the individual dose furthercomprises at least one carrier.
 135. The pharmaceutical kit of claim134, wherein the at least one carrier is at least one biologicallyacceptable carrier.
 136. The pharmaceutical kit of claim 135, whereinthe individual dose comprises at least about 0.5 mg to about 100 mg ofthe at least one compound.
 137. The kit of claim 135, wherein theindividual dose comprises at least about 5 mg to about 10 mg of the atleast one compound.
 138. The pharmaceutical kit of claim 135, whereinthe kit further comprises from about 1 to about 60 individual doses.139. The pharmaceutical kit of claim 135, wherein the kit comprises fromabout 10 to about 30 individual doses.
 140. The pharmaceutical kit ofclaim 135, wherein the kit further comprises from about 12 to about 28individual doses.